Variant 2-47478459-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP6_Moderate

The NM_000251.3(MSH2):c.2398C>G(p.Leu800Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L800L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.13

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 links:

MSH2 (HGNC:):

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

BP6

Variant 2-47478459-C-G is Benign according to our data. Variant chr2-47478459-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1790646.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2398C>G	p.Leu800Val	missense_variant	14/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2398C>G	p.Leu800Val	missense_variant	14/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251412

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135876

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.6

L;.;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

N;N;.;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.012

D;D;.;D

Sift4G

Benign

0.089

T;T;.;T

Polyphen

0.64

P;.;.;D

Vest4

0.84

MutPred

0.60

Loss of stability (P = 0.0779);.;Loss of stability (P = 0.0779);Loss of stability (P = 0.0779);

MVP

0.94

MPC

0.033

ClinPred

0.87

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.56

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over