2-47512412-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The ENST00000406134.5(MSH2):c.2744A>G(p.Gln915Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,608,286 control chromosomes in the GnomAD database, including 131,626 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.46 ( 17425 hom., cov: 32)

Exomes 𝑓: 0.39 ( 114201 hom. )

Consequence

MSH2
ENST00000406134.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 0.310

Publications

23 publications found

Variant links:

COSMIC-nc: COSV100009561

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 was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.0538463E-6).

BP6

Variant 2-47512412-A-G is Benign according to our data. Variant chr2-47512412-A-G is described in ClinVar as Benign. ClinVar VariationId is 41867.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406134.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNK12	NM_022055.2	MANE Select	c.*8495T>C		3_prime_UTR	Exon 2 of 2	NP_071338.1
MSH2	NM_001406674.1		c.2744A>G	p.Gln915Arg	missense	Exon 16 of 18	NP_001393603.1
MSH2	NM_001406631.1		c.2744A>G	p.Gln915Arg	missense	Exon 16 of 18	NP_001393560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSH2	ENST00000406134.5	TSL:1	c.2744A>G	p.Gln915Arg	missense	Exon 16 of 16	ENSP00000384199.1
KCNK12	ENST00000327876.5	TSL:1 MANE Select	c.*8495T>C		3_prime_UTR	Exon 2 of 2	ENSP00000327611.3
MSH2	ENST00000645506.1		c.2744A>G	p.Gln915Arg	missense	Exon 16 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes

AF:

0.463

AC:

70244

AN:

151836

Hom.:

17404

Cov.:

show subpopulations

Gnomad AFR

AF:

0.614

Gnomad AMI

AF:

0.522

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.332

Gnomad EAS

AF:

0.658

Gnomad SAS

AF:

0.432

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.377

Gnomad OTH

AF:

0.424

GnomAD2 exomes

AF:

0.421

AC:

98765

AN:

234612

AF XY:

0.418

show subpopulations

Gnomad AFR exome

AF:

0.608

Gnomad AMR exome

AF:

0.333

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.682

Gnomad FIN exome

AF:

0.498

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.403

GnomAD4 exome

AF:

0.390

AC:

568429

AN:

1456328

Hom.:

114201

Cov.:

AF XY:

0.391

AC XY:

282997

AN XY:

723972

show subpopulations

African (AFR)

AF:

0.620

AC:

20731

AN:

33442

American (AMR)

AF:

0.341

AC:

15004

AN:

44054

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8803

AN:

26056

East Asian (EAS)

AF:

0.621

AC:

24578

AN:

39580

South Asian (SAS)

AF:

0.426

AC:

36456

AN:

85484

European-Finnish (FIN)

AF:

0.500

AC:

25996

AN:

52026

Middle Eastern (MID)

AF:

0.389

AC:

2236

AN:

5746

European-Non Finnish (NFE)

AF:

0.369

AC:

409360

AN:

1109702

Other (OTH)

AF:

0.419

AC:

25265

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

17251

34502

51754

69005

86256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13148

26296

39444

52592

65740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.463

AC:

70321

AN:

151958

Hom.:

17425

Cov.:

AF XY:

0.466

AC XY:

34602

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.614

AC:

25463

AN:

41448

American (AMR)

AF:

0.384

AC:

5865

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

1151

AN:

3462

East Asian (EAS)

AF:

0.657

AC:

3381

AN:

5150

South Asian (SAS)

AF:

0.432

AC:

2078

AN:

4812

European-Finnish (FIN)

AF:

0.499

AC:

5273

AN:

10572

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.377

AC:

25625

AN:

67932

Other (OTH)

AF:

0.424

AC:

892

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1802

3604

5407

7209

9011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.427

Hom.:

10910

Bravo

AF:

0.459

TwinsUK

AF:

0.362

AC:

1343

ALSPAC

AF:

0.360

AC:

1388

ESP6500AA

AF:

0.583

AC:

1021

ESP6500EA

AF:

0.362

AC:

1440

ExAC

AF:

0.422

AC:

48866

Asia WGS

AF:

0.548

AC:

1904

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.87

(source)

DANN

Benign

0.43

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0000071

MetaSVM

Benign

-0.97

PhyloP100

0.31

PROVEAN

Benign

-0.37

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.015

ClinPred

0.0050

GERP RS

-3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over