chr2-47678251-C-G

Position:

• chr2-47678251-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001406633.1(MSH2):​c.2897C>G​(p.Pro966Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 456,544 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0076 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: MSH2 NM_001406633.1 missense, splice_region
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.295

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0076 (1157/152152) while in subpopulation AFR AF= 0.0243 (1009/41508). AF 95% confidence interval is 0.0231. There are 27 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_001406633.1	c.2897C>G	p.Pro966Arg	missense_variant, splice_region_variant	18/19		NP_001393562.1
MSH2	NM_001406637.1	c.2753-29932C>G		intron_variant			NP_001393566.1
MSH2	NR_176241.1	n.3099C>G		splice_region_variant, non_coding_transcript_exon_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1135 AN: 152034 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00271 AC: 364 AN: 134504 Hom.: 1 AF XY: 0.00218 AC XY: 160 AN XY: 73250

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0139

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000757

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00154 AC: 469 AN: 304392 Hom.: 3 Cov.: 0 AF XY: 0.00126 AC XY: 218 AN XY: 173336

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0133

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00760 AC: 1157 AN: 152152 Hom.: 27 Cov.: 32 AF XY: 0.00734 AC XY: 546 AN XY: 74394

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.000126 Hom.: 29

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.74
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17036817; hg19: chr2-47905390;