2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant names:

• chr2-47806751-C-CT
• rs59056100
• NM_000179.3:c.4002-10dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000179.3(MSH6):​c.4002-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (612 hom., cov: 0)
  • Exomes 𝑓: 0.093 (39 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.08
• Publications: 0 publications found

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]

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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-47806751-C-CT is Benign according to our data. Variant chr2-47806751-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 801709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-10dupT		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1366dupA		downstream_gene_variant		ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-10dupT		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1366dupA		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 12644 AN: 138334 Hom.: 611 Cov.: 0

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.0822

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0642

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0839

GnomAD4 exome AF: 0.0927 AC: 119655 AN: 1290418 Hom.: 39 Cov.: 0 AF XY: 0.0905 AC XY: 58332 AN XY: 644382

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0543 AC: 1508 AN: 27796

American (AMR) AF: 0.0516 AC: 1863 AN: 36116

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1438 AN: 23976

East Asian (EAS) AF: 0.0327 AC: 1120 AN: 34272

South Asian (SAS) AF: 0.0590 AC: 4434 AN: 75168

European-Finnish (FIN) AF: 0.0596 AC: 2529 AN: 42440

Middle Eastern (MID) AF: 0.0502 AC: 258 AN: 5144

European-Non Finnish (NFE) AF: 0.103 AC: 102111 AN: 991910

Other (OTH) AF: 0.0820 AC: 4394 AN: 53596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0914 AC: 12648 AN: 138388 Hom.: 612 Cov.: 0 AF XY: 0.0868 AC XY: 5799 AN XY: 66822

African (AFR) AF: 0.0675 AC: 2568 AN: 38042

American (AMR) AF: 0.0788 AC: 1070 AN: 13584

Ashkenazi Jewish (ASJ) AF: 0.0822 AC: 273 AN: 3320

East Asian (EAS) AF: 0.0413 AC: 182 AN: 4406

South Asian (SAS) AF: 0.0682 AC: 288 AN: 4224

European-Finnish (FIN) AF: 0.0605 AC: 482 AN: 7968

Middle Eastern (MID) AF: 0.0667 AC: 18 AN: 270

European-Non Finnish (NFE) AF: 0.118 AC: 7511 AN: 63806

Other (OTH) AF: 0.0838 AC: 159 AN: 1898

Alfa AF: 0.0446 Hom.: 174

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Nov 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 5 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Jul 21, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890;