rs4583514

Positions:

• chr2-47476746-G-A
• chr2-47476746-G-C
• chr2-47476746-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000251.3(MSH2):​c.2210+175G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,072 control chromosomes in the GnomAD database, including 21,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (21097 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.24

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-47476746-G-A is Benign according to our data. Variant chr2-47476746-G-A is described in ClinVar as [Benign]. Clinvar id is 676957.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2210+175G>A		intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2210+175G>A		intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76094 AN: 151952 Hom.: 21067 Cov.: 32

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.455

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.501 AC: 76180 AN: 152072 Hom.: 21097 Cov.: 32 AF XY: 0.503 AC XY: 37360 AN XY: 74326

Gnomad4 AFR AF: 0.734

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.665

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.384

Gnomad4 OTH AF: 0.455

Alfa AF: 0.419 Hom.: 5874

Bravo AF: 0.503

Asia WGS AF: 0.555 AC: 1928 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.065
DANN	Benign	0.49

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: rs4583514; hg19: chr2-47703885;