21-43055686-T-C

Variant names:

• chr21-43055686-T-C
• rs2124461
• NM_000071.3:c.1552+1117A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):​c.1552+1117A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (20895 hom., cov: 11)
  • Exomes 𝑓: 0.68 (7778 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.692
• Publications: 10 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.1552+1117A>G		intron	N/A	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1552+1117A>G		intron	N/A	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1552+1117A>G		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.1552+1117A>G		intron	N/A	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1552+1117A>G		intron	N/A	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1552+1117A>G		intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 58571 AN: 92516 Hom.: 20885 Cov.: 11

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.495

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.603

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.679 AC: 21371 AN: 31452 Hom.: 7778 Cov.: 0 AF XY: 0.673 AC XY: 11758 AN XY: 17480

African (AFR) AF: 0.721 AC: 215 AN: 298

American (AMR) AF: 0.427 AC: 474 AN: 1110

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 343 AN: 488

East Asian (EAS) AF: 0.689 AC: 423 AN: 614

South Asian (SAS) AF: 0.606 AC: 3646 AN: 6012

European-Finnish (FIN) AF: 0.684 AC: 7367 AN: 10772

Middle Eastern (MID) AF: 0.584 AC: 264 AN: 452

European-Non Finnish (NFE) AF: 0.740 AC: 7941 AN: 10724

Other (OTH) AF: 0.711 AC: 698 AN: 982

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.633 AC: 58605 AN: 92578 Hom.: 20895 Cov.: 11 AF XY: 0.624 AC XY: 27644 AN XY: 44276

African (AFR) AF: 0.663 AC: 12897 AN: 19446

American (AMR) AF: 0.444 AC: 4723 AN: 10630

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 1569 AN: 2512

East Asian (EAS) AF: 0.631 AC: 2295 AN: 3636

South Asian (SAS) AF: 0.519 AC: 1447 AN: 2790

European-Finnish (FIN) AF: 0.642 AC: 3679 AN: 5728

Middle Eastern (MID) AF: 0.510 AC: 105 AN: 206

European-Non Finnish (NFE) AF: 0.674 AC: 30864 AN: 45818

Other (OTH) AF: 0.600 AC: 741 AN: 1236

Alfa AF: 0.664 Hom.: 4324

Asia WGS AF: 0.606 AC: 2109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.52
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs2124461;

hg19: chr21-44475796;