2-47791154-TTGTGTGTGTGTG-TTGTGTGTGTGTGTGTG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_000179.3(MSH6):c.457+50_457+53dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,317,924 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650

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 Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000844 (127/150558) while in subpopulation AFR AF= 0.00204 (84/41160). AF 95% confidence interval is 0.00169. There are 1 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.457+50_457+53dup		intron_variant		ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.457+50_457+53dup		intron_variant		1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.000831 AC: 125 AN: 150456 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000634

Gnomad FIN AF: 0.0000969

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.000973

GnomAD4 exome AF: 0.000338 AC: 394 AN: 1167366 Hom.: 0 Cov.: 15 AF XY: 0.000353 AC XY: 207 AN XY: 586420

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000804

Gnomad4 SAS exome AF: 0.000668

Gnomad4 FIN exome AF: 0.0000869

Gnomad4 NFE exome AF: 0.000251

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000844 AC: 127 AN: 150558 Hom.: 1 Cov.: 32 AF XY: 0.000884 AC XY: 65 AN XY: 73516

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000863

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000635

Gnomad4 FIN AF: 0.0000969

Gnomad4 NFE AF: 0.000356

Gnomad4 OTH AF: 0.000963

ClinVar

Not reported in ClinVar

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: rs397839804; hg19: chr2-48018293;