2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTT

Variant names:

• chr2-47806751-C-CTTT
• rs59056100
• NM_000179.3:c.4002-12_4002-10dupTTT

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.4002-12_4002-10dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.018 (68 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• 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-CTTT is Benign according to our data. Variant chr2-47806751-C-CTTT is described in ClinVar as Benign. ClinVar VariationId is 89511.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-12_4002-10dupTTT		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1364_*1366dupAAA		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.4002-12_4002-10dupTTT		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1364_*1366dupAAA		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2458 AN: 138350 Hom.: 68 Cov.: 0

Gnomad AFR AF: 0.0605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.0117

GnomAD4 exome AF: 0.00121 AC: 1578 AN: 1304908 Hom.: 0 Cov.: 0 AF XY: 0.00112 AC XY: 730 AN XY: 651616

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

African (AFR) AF: 0.0335 AC: 921 AN: 27488

American (AMR) AF: 0.00137 AC: 50 AN: 36364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24234

East Asian (EAS) AF: 0.00 AC: 0 AN: 34562

South Asian (SAS) AF: 0.0000658 AC: 5 AN: 75938

European-Finnish (FIN) AF: 0.0000467 AC: 2 AN: 42868

Middle Eastern (MID) AF: 0.00174 AC: 9 AN: 5176

European-Non Finnish (NFE) AF: 0.000482 AC: 484 AN: 1004160

Other (OTH) AF: 0.00198 AC: 107 AN: 54118

⚠️ 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: 0.0178 AC: 2462 AN: 138404 Hom.: 68 Cov.: 0 AF XY: 0.0175 AC XY: 1169 AN XY: 66832

African (AFR) AF: 0.0604 AC: 2299 AN: 38034

American (AMR) AF: 0.00692 AC: 94 AN: 13584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4408

South Asian (SAS) AF: 0.00 AC: 0 AN: 4228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7956

Middle Eastern (MID) AF: 0.00370 AC: 1 AN: 270

European-Non Finnish (NFE) AF: 0.000721 AC: 46 AN: 63834

Other (OTH) AF: 0.0116 AC: 22 AN: 1900

Alfa AF: 0.000509 Hom.: 174

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

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

- -

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% -

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890;