rs192232907

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBP6

The NM_000071.3(CBS):c.215A>T(p.Lys72Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K72K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000049 ( 0 hom., cov: 5)

Exomes 𝑓: 0.00027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 1.02

Publications

5 publications found

Variant links:

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

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000071.3

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.007154703).

BP6

Variant 21-43068610-T-A is Benign according to our data. Variant chr21-43068610-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212883.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.215A>T	p.Lys72Ile	missense_variant	Exon 4 of 17	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.215A>T	p.Lys72Ile	missense_variant	Exon 4 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000489

AC:

AN:

40890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00106

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:

0.000626

AC:

157

AN:

250818

AF XY:

0.000553

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00740

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000270

AC:

100

AN:

371044

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

AN XY:

204022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8682

American (AMR)

AF:

0.00

AC:

AN:

22734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12730

East Asian (EAS)

AF:

0.00290

AC:

AN:

25884

South Asian (SAS)

AF:

0.000281

AC:

AN:

46232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1592

European-Non Finnish (NFE)

AF:

0.0000284

AC:

AN:

211432

Other (OTH)

AF:

0.000299

AC:

AN:

20046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000489

AC:

AN:

40898

Hom.:

Cov.:

AF XY:

0.0000520

AC XY:

AN XY:

19226

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

7650

American (AMR)

AF:

0.00

AC:

AN:

6104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1294

East Asian (EAS)

AF:

0.00107

AC:

AN:

1872

South Asian (SAS)

AF:

0.00

AC:

AN:

1328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

19210

Other (OTH)

AF:

0.00

AC:

AN:

588

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000893

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000618

AC:

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 13, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The K72I variant of uncertain significance in the CBS gene has been reported previously in one Chinese individual with severe homocystinuria who harbored a second variant in the CBS gene (Li et al., 2018). This variant has also been identified both independently of and in conjunction with additional cardiogenetic variants in several individuals referred for TAAD / Marfan syndrome genetic testing at GeneDx. However, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The K72I variant is observed 139/18,848 (0.74%) alleles from individuals of East Asian ancestry in large population cohorts (Lek et al., 2016). The K72I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. -

Feb 23, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CBS c.215A>T; p.Lys72Ile variant (rs192232907) is reported in the literature in an individual affected with coronary artery dissection and another individual affected with homocystinuria (Kaadan 2018, Li 2018). The individual affected with homocystinuria also carried a second missense variant, although the clinical significance of the second variant was not demonstrated (Li 2018). The p.Lys72Ile variant is found in the East Asian population with an overall allele frequency of 0.76% (151/19924 alleles) in the Genome Aggregation Database. The lysine at codon 72 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys72Ile variant is uncertain at this time. References: Kaadan et al. Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection. Circ Genom Precis Med. 2018 Apr;11(4):e001933. Li et al. Eight novel mutations of CBS gene in nine Chinese patients with classical homocystinuria. World J Pediatr. 2018 Apr;14(2):197-203. -

Classic homocystinuria

Uncertain:1Benign:1

May 30, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Connective tissue disorder

Uncertain:1

Nov 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CBS c.215A>T (p.Lys72Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 281244 control chromosomes (gnomAD), predominantly at a frequency of 0.0076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

May 26, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CBS-related disorder

Benign:1

Jul 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

D;D;D;D;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.81

.;.;.;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0072

T;T;T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.1

M;M;M;M;.

PhyloP100

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

N;N;N;N;D

REVEL

Uncertain

0.36

Sift

Benign

0.21

T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.0

B;B;B;B;.

Vest4

0.40

MVP

0.68

MPC

0.62

ClinPred

0.019

GERP RS

3.6

Varity_R

0.68

gMVP

0.62

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over