2-47797737-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000179.3(MSH6):c.628-874C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 157,010 control chromosomes in the GnomAD database, including 33,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.65 ( 33087 hom., cov: 32)

Exomes 𝑓: 0.61 ( 900 hom. )

Consequence

MSH6
NM_000179.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:2

Conservation

PhyloP100: -0.939

Publications

14 publications found

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:

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 links:

RPL36AP15 (HGNC:36648): (ribosomal protein L36a pseudogene 15)

RPL36AP15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-47797737-C-T is Benign according to our data. Variant chr2-47797737-C-T is described in ClinVar as Benign. ClinVar VariationId is 89544.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.628-874C>T		intron_variant	Intron 3 of 9	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.628-874C>T		intron_variant	Intron 3 of 9	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98457

AN:

151936

Hom.:

33067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.807

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.865

Gnomad SAS

AF:

0.704

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.575

Gnomad OTH

AF:

0.629

GnomAD4 exome

AF:

0.610

AC:

3023

AN:

4956

Hom.:

900

AF XY:

0.604

AC XY:

1842

AN XY:

3048

show subpopulations

African (AFR)

AF:

0.817

AC:

103

AN:

126

American (AMR)

AF:

0.605

AC:

322

AN:

532

Ashkenazi Jewish (ASJ)

AF:

0.792

AC:

AN:

East Asian (EAS)

AF:

0.843

AC:

263

AN:

312

South Asian (SAS)

AF:

0.697

AC:

453

AN:

650

European-Finnish (FIN)

AF:

0.505

AC:

215

AN:

426

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.575

AC:

1508

AN:

2624

Other (OTH)

AF:

0.504

AC:

119

AN:

236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.648

AC:

98517

AN:

152054

Hom.:

33087

Cov.:

AF XY:

0.645

AC XY:

47911

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.807

AC:

33475

AN:

41492

American (AMR)

AF:

0.580

AC:

8849

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

2503

AN:

3470

East Asian (EAS)

AF:

0.865

AC:

4478

AN:

5176

South Asian (SAS)

AF:

0.702

AC:

3379

AN:

4812

European-Finnish (FIN)

AF:

0.444

AC:

4689

AN:

10568

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.575

AC:

39041

AN:

67952

Other (OTH)

AF:

0.629

AC:

1325

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1719

3438

5156

6875

8594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.614

Hom.:

71744

Bravo

AF:

0.666

Asia WGS

AF:

0.768

AC:

2672

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome

Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1% -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.64

(source)

DANN

Benign

0.43

PhyloP100

-0.94

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over