rs555751528

chr21-43065465-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):c.588G>C(p.Arg196Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R196R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 4)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.887

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048401684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.588G>C	p.Arg196Ser	missense_variant	7/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.588G>C	p.Arg196Ser	missense_variant	7/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249442 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135040

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 4

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The p.R196S variant (also known as c.588G>C), located in coding exon 5 of the CBS gene, results from a G to C substitution at nucleotide position 588. The arginine at codon 196 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Classic homocystinuria Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 09, 2020

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

This sequence change replaces arginine with serine at codon 196 of the CBS protein (p.Arg196Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs555751528, ExAC 0.06%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Uncertain	0.64	D;D;D;D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-1.1	N;N;N;N
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.17	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.63	T;T;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.48
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.24
MPC		0.40
ClinPred		0.027	T
GERP RS		-1.1
Varity_R		0.70
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs555751528; hg19: chr21-44485575;