rs121964970

Variant names:

• chr21-43065645-C-A
• rs121964970
• NM_000071.3:c.502G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43065645-C-A
• chr21-43065645-C-G
• chr21-43065645-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3_Moderate

The NM_000071.3(CBS):​c.502G>T​(p.Val168Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V168M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78
• Publications: 14 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43065645-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.502G>T	p.Val168Leu	missense_variant	Exon 6 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.502G>T	p.Val168Leu	missense_variant	Exon 6 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000535 AC: 1 AN: 186900 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00000469 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;M;.
PhyloP100		6.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.84	P;P;P;P;.
Vest4		0.90
MutPred		0.75		Loss of catalytic residue at V168 (P = 0.0688);Loss of catalytic residue at V168 (P = 0.0688);Loss of catalytic residue at V168 (P = 0.0688);Loss of catalytic residue at V168 (P = 0.0688);Loss of catalytic residue at V168 (P = 0.0688);
MVP		0.95
MPC		1.0
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.85
Mutation Taster		=7/93	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: rs121964970; hg19: chr21-44485755;