2-47783419-C-A

Position:

chr2-47783419-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000234420.11(MSH6):c.186C>A(p.Arg62=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,511,208 control chromosomes in the GnomAD database, including 22,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. R62R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.13 ( 1544 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21116 hom. )

Consequence

MSH6
ENST00000234420.11 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:21

Conservation

PhyloP100: -0.0560

Variant links:

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 2-47783419-C-A is Benign according to our data. Variant chr2-47783419-C-A is described in ClinVar as [Benign]. Clinvar id is 36584.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47783419-C-A is described in Lovd as [Benign]. Variant chr2-47783419-C-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.056 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.186C>A	p.Arg62=	synonymous_variant	1/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.186C>A	p.Arg62=	synonymous_variant	1/10	1	NM_000179.3	ENSP00000234420	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19171

AN:

152048

Hom.:

1546

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0530

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.000971

Gnomad SAS

AF:

0.0596

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.166

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.144

GnomAD3 exomes

AF:

0.144

AC:

16491

AN:

114188

Hom.:

1414

AF XY:

0.146

AC XY:

9338

AN XY:

63964

show subpopulations

Gnomad AFR exome

AF:

0.0571

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.000400

Gnomad SAS exome

AF:

0.0847

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.170

AC:

231000

AN:

1359046

Hom.:

21116

Cov.:

AF XY:

0.167

AC XY:

112006

AN XY:

668872

show subpopulations

Gnomad4 AFR exome

AF:

0.0439

Gnomad4 AMR exome

AF:

0.0978

Gnomad4 ASJ exome

AF:

0.167

Gnomad4 EAS exome

AF:

0.000413

Gnomad4 SAS exome

AF:

0.0772

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.190

Gnomad4 OTH exome

AF:

0.153

GnomAD4 genome

AF:

0.126

AC:

19169

AN:

152162

Hom.:

1544

Cov.:

AF XY:

0.122

AC XY:

9103

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0531

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.153

Gnomad4 EAS

AF:

0.000974

Gnomad4 SAS

AF:

0.0597

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.184

Gnomad4 OTH

AF:

0.142

Alfa

AF:

0.109

Hom.:

302

Bravo

AF:

0.126

Asia WGS

AF:

0.0410

AC:

143

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:11

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 22, 2011	This variant is classified as benign because it does not result in an amino acid change and is common in the general population (rs1042820, MAF >1%). -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Lynch syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lynch syndrome

Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2015	- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.7

DANN

Benign

0.80

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over