rs1981928

chr2-47445336-T-Achr2-47445336-T-G

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.1277-212T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,038 control chromosomes in the GnomAD database, including 13,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.39 (13452 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.285

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=-0.81).
• BP6: Variant 2-47445336-T-A is Benign according to our data. Variant chr2-47445336-T-A is described in ClinVar as [Benign]. Clinvar id is 90603.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47445336-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1277-212T>A		intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1277-212T>A		intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59657 AN: 151920 Hom.: 13429 Cov.: 32

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.358

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

GnomAD4 genome AF: 0.393 AC: 59729 AN: 152038 Hom.: 13452 Cov.: 32 AF XY: 0.396 AC XY: 29427 AN XY: 74316

Gnomad4 AFR AF: 0.595

Gnomad4 AMR AF: 0.339

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.655

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.357

Alfa AF: 0.355 Hom.: 1320

Bravo AF: 0.397

Asia WGS AF: 0.497 AC: 1724 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

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	-0.81
Cadd	Benign	1.9
Dann	Benign	0.77

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: rs1981928; hg19: chr2-47672475;