rs1060500683

Variant names:

• chr21-43065431-A-G
• rs1060500683
• NM_000071.3:c.622T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000071.3(CBS):​c.622T>C​(p.Trp208Arg) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W208C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 5)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.79
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.

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.622T>C	p.Trp208Arg	missense	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.622T>C	p.Trp208Arg	missense	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.622T>C	p.Trp208Arg	missense	Exon 7 of 18	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.622T>C	p.Trp208Arg	missense	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.622T>C	p.Trp208Arg	missense	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.622T>C	p.Trp208Arg	missense	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 19664 Hom.: 0 Cov.: 5

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: 0.00000400 AC: 1 AN: 249888 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000455 AC: 2 AN: 439874 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 235112

African (AFR) AF: 0.00 AC: 0 AN: 13644

American (AMR) AF: 0.00 AC: 0 AN: 30836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14778

East Asian (EAS) AF: 0.00 AC: 0 AN: 31340

South Asian (SAS) AF: 0.00 AC: 0 AN: 54406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1890

European-Non Finnish (NFE) AF: 0.00000416 AC: 1 AN: 240616

Other (OTH) AF: 0.0000409 AC: 1 AN: 24452

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 19664 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 9262

African (AFR) AF: 0.00 AC: 0 AN: 4798

American (AMR) AF: 0.00 AC: 0 AN: 2094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 534

East Asian (EAS) AF: 0.00 AC: 0 AN: 984

South Asian (SAS) AF: 0.00 AC: 0 AN: 340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 38

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 9196

Other (OTH) AF: 0.00 AC: 0 AN: 186

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Benign	0.84
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	-2.3	N
PhyloP100		7.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.60
Sift	Benign	0.74	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.87
MutPred		0.45		Gain of disorder (P = 0.0066)
MVP		0.68
MPC		0.62
ClinPred		0.32	T
GERP RS		4.7
Varity_R		0.68
gMVP		0.91
Mutation Taster		=19/81	disease causing

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: rs1060500683; hg19: chr21-44485541;