chr2-47806751-CTTT-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000179.3(MSH6):c.4002-12_4002-10delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,437,648 control chromosomes in the GnomAD database, including 72 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 64 hom., cov: 0)

Exomes 𝑓: 0.0085 ( 8 hom. )

Consequence

MSH6
NM_000179.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.167

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-47806751-CTTT-C is Benign according to our data. Variant chr2-47806751-CTTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1231970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47806751-CTTT-C is described in Lovd as [Benign]. Variant chr2-47806751-CTTT-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.4002-12_4002-10delTTT		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9
FBXO11	NM_001190274.2 link	c.1364_1366delAAA		downstream_gene_variant		ENST00000403359.8	NP_001177203.1	Q86XK2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.4002-12_4002-10delTTT		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5		P52701-1
FBXO11	ENST00000403359.8 link	c.1364_1366delAAA		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4		Q86XK2-1

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3180

AN:

138366

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0620

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0105

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000235

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00338

Gnomad NFE

AF:

0.00721

Gnomad OTH

AF:

0.0233

GnomAD4 exome

AF:

0.00848

AC:

11023

AN:

1299230

Hom.:

AF XY:

0.00828

AC XY:

5370

AN XY:

648812

show subpopulations

Gnomad4 AFR exome

AF:

0.0614

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0107

Gnomad4 EAS exome

AF:

0.00105

Gnomad4 SAS exome

AF:

0.00180

Gnomad4 FIN exome

AF:

0.00949

Gnomad4 NFE exome

AF:

0.00753

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.0231

AC:

3192

AN:

138418

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1517

AN XY:

66832

show subpopulations

Gnomad4 AFR

AF:

0.0621

Gnomad4 AMR

AF:

0.0146

Gnomad4 ASJ

AF:

0.0105

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000237

Gnomad4 FIN

AF:

0.0112

Gnomad4 NFE

AF:

0.00719

Gnomad4 OTH

AF:

0.0232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Jun 08, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jul 08, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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