rs6544991

Positions:

• chr2-47485641-A-C
• chr2-47485641-A-G
• chr2-47485641-A-T

Variant summary

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

The ENST00000406134.5(MSH2):​c.2634+4770A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,124 control chromosomes in the GnomAD database, including 3,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.21 (3692 hom., cov: 32)
• Consequence: MSH2 ENST00000406134.5 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.70

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=-0.83).
• BP6: Variant 2-47485641-A-C is Benign according to our data. Variant chr2-47485641-A-C is described in ClinVar as [Benign]. Clinvar id is 90481.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47485641-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_001406631.1	c.2634+4770A>C		intron_variant			NP_001393560.1
MSH2	NM_001406632.1	c.2634+4770A>C		intron_variant			NP_001393561.1
MSH2	NM_001406633.1	c.2634+4770A>C		intron_variant			NP_001393562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000406134.5	c.2634+4770A>C		intron_variant		1		ENSP00000384199
MSH2	ENST00000645506.1	c.2634+4770A>C		intron_variant				ENSP00000495455
MSH2	ENST00000644092.1	c.*934+4770A>C		intron_variant, NMD_transcript_variant				ENSP00000496351

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32447 AN: 152006 Hom.: 3693 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.213 AC: 32466 AN: 152124 Hom.: 3692 Cov.: 32 AF XY: 0.218 AC XY: 16190 AN XY: 74382

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.194

Alfa AF: 0.172 Hom.: 2432

Bravo AF: 0.209

Asia WGS AF: 0.264 AC: 917 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

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% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.63

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6544991; hg19: chr2-47712780;