2-47408384-CTTT-CT

Position:

• chr2-47408384-CTTT-CT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000251.3(MSH2):​c.212-5_212-4del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 1,330,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: MSH2 NM_000251.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.95

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 -8 ACMG points.

• BP6: Variant 2-47408384-CTT-C is Benign according to our data. Variant chr2-47408384-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1697887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.212-5_212-4del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.212-5_212-4del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000278 AC: 4 AN: 144084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000512

GnomAD4 exome AF: 0.000774 AC: 919 AN: 1186636 Hom.: 0 AF XY: 0.000759 AC XY: 452 AN XY: 595292

Gnomad4 AFR exome AF: 0.000762

Gnomad4 AMR exome AF: 0.000944

Gnomad4 ASJ exome AF: 0.000353

Gnomad4 EAS exome AF: 0.000406

Gnomad4 SAS exome AF: 0.000484

Gnomad4 FIN exome AF: 0.000634

Gnomad4 NFE exome AF: 0.000831

Gnomad4 OTH exome AF: 0.000720

GnomAD4 genome AF: 0.0000277 AC: 4 AN: 144146 Hom.: 0 Cov.: 31 AF XY: 0.0000429 AC XY: 3 AN XY: 69984

Gnomad4 AFR AF: 0.0000507

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000111

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000509

Alfa AF: 0.00192 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs746333570; hg19: chr2-47635523;