chr21-43066310-C-T

Variant names:

• chr21-43066310-C-T
• rs374593242
• NM_000071.3:c.384G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Very_Strong BP7 BS2_Supporting

The NM_000071.3(CBS):​c.384G>A​(p.Glu128Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 12)
  • Exomes 𝑓: 0.000020 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.389
• Publications: 3 publications found

Genes affected

CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

CBS Gene-Disease associations (from GenCC):

• classic homocystinuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 21-43066310-C-T is Benign according to our data. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066310-C-T is described in CliVar as Likely_benign. Clinvar id is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.389 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.384G>A	p.Glu128Glu	synonymous_variant	Exon 5 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.384G>A	p.Glu128Glu	synonymous_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.0000221 AC: 2 AN: 90440 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.000135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251054 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000200 AC: 18 AN: 900284 Hom.: 3 Cov.: 13 AF XY: 0.0000173 AC XY: 8 AN XY: 463522

African (AFR) AF: 0.00 AC: 0 AN: 15316

American (AMR) AF: 0.0000240 AC: 1 AN: 41580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20114

East Asian (EAS) AF: 0.000107 AC: 4 AN: 37524

South Asian (SAS) AF: 0.00 AC: 0 AN: 69962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 635636

Other (OTH) AF: 0.000319 AC: 13 AN: 40718

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000221 AC: 2 AN: 90440 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 43828

African (AFR) AF: 0.000135 AC: 2 AN: 14838

American (AMR) AF: 0.00 AC: 0 AN: 10510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4210

South Asian (SAS) AF: 0.00 AC: 0 AN: 2922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 46472

Other (OTH) AF: 0.00 AC: 0 AN: 1232

Alfa AF: 0.000153 Hom.: 0

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Apr 30, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.3
DANN	Benign	0.93
PhyloP100		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374593242; hg19: chr21-44486420;