2-47806842-TTTGA-TTTGATTGA

Variant names:

• chr2-47806842-T-TTTGA
• rs55740729
• NM_000179.3:c.4068_4071dupGATT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.4068_4071dupGATT​(p.Lys1358AspfsTer2) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00079 in 1,612,404 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. K1358K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (24 hom.)
• Consequence: MSH6 NM_000179.3 frameshift, stop_gained
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:25 O:1
• Conservation: PhyloP100: 0.124
• Publications: 23 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00269 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 2-47806842-T-TTTGA is Benign according to our data. Variant chr2-47806842-T-TTTGA is described in ClinVar as Likely_benign. ClinVar VariationId is 89518.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00109 (166/151998) while in subpopulation EAS AF = 0.0286 (148/5182). AF 95% confidence interval is 0.0248. There are 2 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.4068_4071dupGATT	p.Lys1358AspfsTer2	frameshift stop_gained	Exon 10 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4164_4167dupGATT	p.Lys1390AspfsTer2	frameshift stop_gained	Exon 11 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.4074_4077dupGATT	p.Lys1360AspfsTer2	frameshift stop_gained	Exon 10 of 10	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.4068_4071dupGATT	p.Lys1358AspfsTer2	frameshift stop_gained	Exon 10 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3415_*3418dupGATT		non_coding_transcript_exon	Exon 9 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*3415_*3418dupGATT		3_prime_UTR	Exon 9 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 151880 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00253 AC: 636 AN: 251058 AF XY: 0.00230

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000759 AC: 1108 AN: 1460406 Hom.: 24 Cov.: 32 AF XY: 0.000752 AC XY: 546 AN XY: 726538

African (AFR) AF: 0.0000897 AC: 3 AN: 33428

American (AMR) AF: 0.000112 AC: 5 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0227 AC: 898 AN: 39640

South Asian (SAS) AF: 0.000650 AC: 56 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111078

Other (OTH) AF: 0.00220 AC: 133 AN: 60334

GnomAD4 genome AF: 0.00109 AC: 166 AN: 151998 Hom.: 2 Cov.: 31 AF XY: 0.00135 AC XY: 100 AN XY: 74306

African (AFR) AF: 0.000121 AC: 5 AN: 41460

American (AMR) AF: 0.000131 AC: 2 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000588 Hom.: 0

Asia WGS AF: 0.0110 AC: 39 AN: 3472

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	not specified (5)
-	-	2	Lynch syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colon cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (1)
-	1	-	Lynch syndrome 1 (1)
-	-	1	Lynch syndrome 5 (1)
-	-	1	Sigmoid colon cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=104/96	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs55740729; hg19: chr2-48033981; COSMIC: COSV52273912; COSMIC: COSV52273912;