chr2-47403338-C-A

Position:

• chr2-47403338-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000251.3(MSH2):​c.147C>A​(p.Asp49Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.816

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.147C>A	p.Asp49Glu	missense_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.147C>A	p.Asp49Glu	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000431 AC: 1 AN: 231780 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126714

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: 0.00000965

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Pathogenic	0.78
Sift	Benign	0.055	T;.;D
Sift4G	Uncertain	0.033	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.82
MutPred		0.89		Gain of disorder (P = 0.1841);Gain of disorder (P = 0.1841);Gain of disorder (P = 0.1841);
MVP		0.98
MPC		0.035
ClinPred		0.99	D
GERP RS		1.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.89
gMVP		0.74

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: rs730881771; hg19: chr2-47630477;