2-47791154-TTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTGTG

Variant names:

• chr2-47791154-T-TTGTG
• rs397839804
• NM_000179.3:c.457+50_457+53dupTGTG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_000179.3(MSH6):​c.457+50_457+53dupTGTG 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0650
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-47791154-T-TTGTG is Benign according to our data. Variant chr2-47791154-T-TTGTG is described in ClinVar as Likely_benign. ClinVar VariationId is 3765347.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.457+50_457+53dupTGTG		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.553+50_553+53dupTGTG		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.463+44_463+47dupTGTG		intron	N/A	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.457+31_457+32insTGTG		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.457+31_457+32insTGTG		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000700002.1		c.457+31_457+32insTGTG		intron	N/A	ENSP00000514750.1

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

African (AFR) AF: 0.00278 AC: 77 AN: 27730

American (AMR) AF: 0.000196 AC: 8 AN: 40824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22166

East Asian (EAS) AF: 0.0000804 AC: 3 AN: 37334

South Asian (SAS) AF: 0.000668 AC: 52 AN: 77808

European-Finnish (FIN) AF: 0.0000869 AC: 4 AN: 46008

Middle Eastern (MID) AF: 0.00121 AC: 6 AN: 4940

European-Non Finnish (NFE) AF: 0.000251 AC: 216 AN: 860846

Other (OTH) AF: 0.000563 AC: 28 AN: 49710

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

African (AFR) AF: 0.00204 AC: 84 AN: 41160

American (AMR) AF: 0.000863 AC: 13 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.000635 AC: 3 AN: 4722

European-Finnish (FIN) AF: 0.0000969 AC: 1 AN: 10320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000356 AC: 24 AN: 67470

Other (OTH) AF: 0.000963 AC: 2 AN: 2076

Alfa AF: 0.000114 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.065
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: rs397839804; hg19: chr2-48018293;