chr2-47480802-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000251.3(MSH2):ā€‹c.2565G>Cā€‹(p.Gln855His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

2
15
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.46
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkc.2565G>C p.Gln855His missense_variant 15/16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.2565G>C p.Gln855His missense_variant 15/161 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461824
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727210
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;.;.;.
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Uncertain
0.090
D
MetaRNN
Uncertain
0.57
D;D;D;D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Uncertain
2.1
M;.;.;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.2
D;D;.;D
REVEL
Uncertain
0.55
Sift
Benign
0.037
D;D;.;D
Sift4G
Uncertain
0.040
D;D;.;D
Polyphen
0.34
B;.;.;P
Vest4
0.62
MutPred
0.33
Loss of solvent accessibility (P = 0.1362);.;Loss of solvent accessibility (P = 0.1362);Loss of solvent accessibility (P = 0.1362);
MVP
0.97
MPC
0.0073
ClinPred
0.61
D
GERP RS
6.0
Varity_R
0.35
gMVP
0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47707941; API