2-47806771-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000179.3(MSH6):c.4002-8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH6
NM_000179.3 splice_region, intron

Scores

Splicing: ADA: 0.00006639

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.932

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-47806771-A-T is Benign according to our data. Variant chr2-47806771-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 234447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.4002-8A>T		splice_region_variant, intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9
FBXO11	NM_001190274.2 link	c.*1347T>A		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.4002-8A>T		splice_region_variant, intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5		P52701-1
FBXO11	ENST00000403359.8 link	c.*1347T>A		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4		Q86XK2-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

151

AN:

138492

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000707

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000410

Gnomad SAS

AF:

0.000219

Gnomad FIN

AF:

0.00533

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.000521

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00122

AC:

1672

AN:

1373894

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

872

AN XY:

682674

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.00183

Gnomad4 EAS exome

AF:

0.000289

Gnomad4 SAS exome

AF:

0.00359

Gnomad4 FIN exome

AF:

0.00652

Gnomad4 NFE exome

AF:

0.000510

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00109

AC:

151

AN:

138568

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

67170

show subpopulations

Gnomad4 AFR

AF:

0.000571

Gnomad4 AMR

AF:

0.0000706

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000411

Gnomad4 SAS

AF:

0.000220

Gnomad4 FIN

AF:

0.00533

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.000516

Alfa

AF:

0.0263

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 5

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 13, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Nov 11, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jul 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.1

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.088

SpliceAI score (max)

0.060

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