rs3764960

chr2-47471245-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000251.3(MSH2):c.1759+183G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 151,926 control chromosomes in the GnomAD database, including 14,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.42 (14848 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.996

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-47471245-G-A is Benign according to our data. Variant chr2-47471245-G-A is described in ClinVar as [Benign]. Clinvar id is 439906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47471245-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1759+183G>A		intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1759+183G>A		intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63516 AN: 151808 Hom.: 14825 Cov.: 32

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.384

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

GnomAD4 genome AF: 0.419 AC: 63588 AN: 151926 Hom.: 14848 Cov.: 32 AF XY: 0.421 AC XY: 31276 AN XY: 74234

Gnomad4 AFR AF: 0.609

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.382

Alfa AF: 0.382 Hom.: 1508

Bravo AF: 0.419

Asia WGS AF: 0.495 AC: 1717 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 02, 2018

- -

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	-0.91
Cadd	Benign	0.29
Dann	Benign	0.21

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: rs3764960; hg19: chr2-47698384;