Variant chr2-47512394-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001406674.1(MSH2):c.2726G>A(p.Arg909Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,611,322 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 32)

Exomes 𝑓: 0.019 ( 334 hom. )

Consequence

MSH2
NM_001406674.1 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -1.53

Variant links:

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 links:

KCNK12 (HGNC:6274): (potassium two pore domain channel subfamily K member 12) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity. [provided by RefSeq, Jul 2008]

KCNK12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003568858).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1799/152234) while in subpopulation NFE AF= 0.0188 (1276/67986). AF 95% confidence interval is 0.0179. There are 15 homozygotes in gnomad4. There are 788 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 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK12	NM_022055.2 link	c.*8513C>T		3_prime_UTR_variant	2/2	ENST00000327876.5	NP_071338.1	Q9HB15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK12	ENST00000327876.5 link	c.*8513C>T		3_prime_UTR_variant	2/2	1	NM_022055.2	ENSP00000327611.3		Q9HB15

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1799

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00698

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0116

AC:

2755

AN:

238202

Hom.:

AF XY:

0.0117

AC XY:

1535

AN XY:

130656

show subpopulations

Gnomad AFR exome

AF:

0.00356

Gnomad AMR exome

AF:

0.00541

Gnomad ASJ exome

AF:

0.0275

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000572

Gnomad FIN exome

AF:

0.00730

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0187

AC:

27336

AN:

1459088

Hom.:

334

Cov.:

AF XY:

0.0182

AC XY:

13196

AN XY:

725636

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.00616

Gnomad4 ASJ exome

AF:

0.0285

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000909

Gnomad4 FIN exome

AF:

0.00799

Gnomad4 NFE exome

AF:

0.0223

Gnomad4 OTH exome

AF:

0.0143

GnomAD4 genome

AF:

0.0118

AC:

1799

AN:

152234

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

788

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00364

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.0294

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00698

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0160

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.0188

AC:

ExAC

AF:

0.0112

AC:

1302

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.020

DANN

Benign

0.40

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.80

PROVEAN

Benign

0.78

.;N

REVEL

Benign

0.19

Sift

Benign

0.60

.;T

Sift4G

Benign

0.60

.;T

Polyphen

0.0

.;B

Vest4

0.024

ClinPred

0.00070

GERP RS

-5.2

Splicing

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