NM_000071.3:c.636C>G

Variant names:

• chr21-43065417-G-C
• rs2298758
• NM_000071.3:c.636C>G

Variant summary

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

The NM_000071.3(CBS):​c.636C>G​(p.Asn212Lys) 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. N212N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.00019 (19 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.783

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=0.051193625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.636C>G	p.Asn212Lys	missense_variant	Exon 7 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.636C>G	p.Asn212Lys	missense_variant	Exon 7 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 250098 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135358

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 SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000187 AC: 84 AN: 448080 Hom.: 19 Cov.: 4 AF XY: 0.000321 AC XY: 77 AN XY: 239924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000406

GnomAD4 genome Cov.: 5

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Classic homocystinuria Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 15, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn212Lys (AAC>AAG): c.636 C>G in exon 7 of the CBS gene (NM_000071.2). A variant of unknown significance has been identified in the CBS gene. To our knowledge, the N212K variant has not been published as a disease-causing mutation nor as a benign polymorphism to our knowledge. The N212K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N212K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is mostly conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense mutation in nearby residue (S217F) has been reported in association with homocystinuria, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.017
DANN	Benign	0.74
DEOGEN2	Uncertain	0.65	D;D;D;D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.91	.;.;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.051	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-1.7	N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.78	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.60
MutPred		0.38		Gain of ubiquitination at N212 (P = 0.0289);Gain of ubiquitination at N212 (P = 0.0289);Gain of ubiquitination at N212 (P = 0.0289);Gain of ubiquitination at N212 (P = 0.0289);
MVP		0.21
MPC		0.40
ClinPred		0.0097	T
GERP RS		-6.6
Varity_R		0.18
gMVP		0.76

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: rs2298758; hg19: chr21-44485527;