rs10495946

Variant names:

• chr2-47686875-G-C
• rs10495946
• NM_001406637.1:c.2753-21308G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47686875-G-C
• chr2-47686875-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001406637.1(MSH2):​c.2753-21308G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 152,088 control chromosomes in the GnomAD database, including 723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.076 (723 hom., cov: 32)
• Consequence: MSH2 NM_001406637.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_001406637.1	c.2753-21308G>C		intron_variant	Intron 16 of 16		NP_001393566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11545 AN: 151970 Hom.: 722 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0857

Gnomad OTH AF: 0.0699

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

GnomAD4 genome AF: 0.0759 AC: 11544 AN: 152088 Hom.: 723 Cov.: 32 AF XY: 0.0774 AC XY: 5752 AN XY: 74362

African (AFR) AF: 0.0249 AC: 1034 AN: 41492

American (AMR) AF: 0.0585 AC: 893 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.332 AC: 1712 AN: 5162

South Asian (SAS) AF: 0.183 AC: 882 AN: 4810

European-Finnish (FIN) AF: 0.0689 AC: 729 AN: 10576

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5829 AN: 67986

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

Alfa AF: 0.0343 Hom.: 28

Bravo AF: 0.0720

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.89
DANN	Benign	0.89
PhyloP100		-0.64

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10495946; hg19: chr2-47914014;