2-47476455-G-C

Position:

• chr2-47476455-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000251.3(MSH2):​c.2094G>C​(p.Glu698Asp) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a strand (size 8) in uniprot entity MSH2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1376063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2094G>C	p.Glu698Asp	missense_variant	13/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2094G>C	p.Glu698Asp	missense_variant	13/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.13	N;.;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.090	N;N;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.80	T;T;.;T
Sift4G	Benign	0.85	T;T;.;T
Polyphen		0.0010	B;.;.;B
Vest4		0.50
MutPred		0.47		Gain of loop (P = 0.2045);.;Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);
MVP		0.97
MPC		0.0067
ClinPred		0.085	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr2-47703594;