2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTT

Position:

• chr2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000234420.11(MSH6):​c.4002-11_4002-10dup variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: MSH6 ENST00000234420.11 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-47806751-C-CTT is Benign according to our data. Variant chr2-47806751-C-CTT is described in ClinVar as [Benign]. Clinvar id is 89510.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00147 (204/138432) while in subpopulation AFR AF= 0.00381 (145/38062). AF 95% confidence interval is 0.0033. There are 2 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-11_4002-10dup		intron_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-11_4002-10dup		intron_variant		1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 204 AN: 138378 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000884

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000905

Gnomad SAS AF: 0.000706

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.000548

Gnomad OTH AF: 0.000530

GnomAD4 exome AF: 0.00241 AC: 3142 AN: 1302236 Hom.: 0 Cov.: 0 AF XY: 0.00226 AC XY: 1470 AN XY: 650256

Gnomad4 AFR exome AF: 0.00923

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.000537

Gnomad4 EAS exome AF: 0.000869

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000724

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00147 AC: 204 AN: 138432 Hom.: 2 Cov.: 0 AF XY: 0.00154 AC XY: 103 AN XY: 66834

Gnomad4 AFR AF: 0.00381

Gnomad4 AMR AF: 0.000883

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000907

Gnomad4 SAS AF: 0.000710

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000548

Gnomad4 OTH AF: 0.000526

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890;