21-43065605-C-T

Variant names:

• chr21-43065605-C-T
• rs186114513
• NM_000071.3:c.531+11G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000071.3(CBS):​c.531+11G>A variant causes a intron 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 0.0 (0 hom., cov: 2)
  • Exomes 𝑓: 0.000055 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.09
• Publications: 0 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: ClinGen, Genomics England PanelApp, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-43065605-C-T is Benign according to our data. Variant chr21-43065605-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.531+11G>A		intron	N/A	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.531+11G>A		intron	N/A	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.531+11G>A		intron	N/A	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.531+11G>A		intron	N/A	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.531+11G>A		intron	N/A	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.531+11G>A		intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 2878 Hom.: 0 Cov.: 2

Gnomad AFR AF: 0.00

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: 0.00428 AC: 833 AN: 194546 AF XY: 0.00424

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00417

Gnomad NFE exome AF: 0.00787

Gnomad OTH exome AF: 0.00377

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000554 AC: 18 AN: 325008 Hom.: 2 Cov.: 0 AF XY: 0.0000586 AC XY: 10 AN XY: 170778

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9906

American (AMR) AF: 0.00 AC: 0 AN: 15570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9410

East Asian (EAS) AF: 0.0000355 AC: 1 AN: 28156

South Asian (SAS) AF: 0.00 AC: 0 AN: 41316

European-Finnish (FIN) AF: 0.0000503 AC: 1 AN: 19888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1338

European-Non Finnish (NFE) AF: 0.0000885 AC: 16 AN: 180700

Other (OTH) AF: 0.00 AC: 0 AN: 18724

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000613571), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2878 Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 1370

African (AFR) AF: 0.00 AC: 0 AN: 524

American (AMR) AF: 0.00 AC: 0 AN: 504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 30

East Asian (EAS) AF: 0.00 AC: 0 AN: 402

South Asian (SAS) AF: 0.00 AC: 0 AN: 236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 20

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 900

Other (OTH) AF: 0.00 AC: 0 AN: 66

Alfa AF: 0.00273 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Classic homocystinuria (2)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.18
DANN	Benign	0.56
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs186114513;

hg19: chr21-44485715;