chr2-47416321-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000251.3(MSH2):​c.968C>A​(p.Ser323Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S323C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

2
11
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47416321-C-A is Pathogenic according to our data. Variant chr2-47416321-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSH2NM_000251.3 linkuse as main transcriptc.968C>A p.Ser323Tyr missense_variant 6/16 ENST00000233146.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.968C>A p.Ser323Tyr missense_variant 6/161 NM_000251.3 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460304
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726622
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.72
D;.;.;.
Eigen
Benign
-0.071
Eigen_PC
Benign
0.043
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.71
D;D;D;D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
1.8
L;.;.;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.1
D;D;.;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.012
D;D;.;D
Sift4G
Benign
0.58
T;T;.;T
Polyphen
0.12
B;.;.;P
Vest4
0.48
MutPred
0.53
Loss of disorder (P = 0.0129);.;Loss of disorder (P = 0.0129);Loss of disorder (P = 0.0129);
MVP
0.94
MPC
0.011
ClinPred
0.97
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.32
gMVP
0.24

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.

Other links and lift over

dbSNP: rs63750732; hg19: chr2-47643460; API