chr2-47795842-G-T

Position:

• chr2-47795842-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000179.3(MSH6):​c.458-52G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,527,276 control chromosomes in the GnomAD database, including 26,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3546 hom., cov: 33)
  • Exomes 𝑓: 0.18 (23314 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.375

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-47795842-G-T is Benign according to our data. Variant chr2-47795842-G-T is described in ClinVar as [Benign]. Clinvar id is 89532.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47795842-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.458-52G>T		intron_variant		ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.458-52G>T		intron_variant		1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31654 AN: 151872 Hom.: 3539 Cov.: 33

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.179 AC: 246499 AN: 1375288 Hom.: 23314 Cov.: 21 AF XY: 0.180 AC XY: 123667 AN XY: 687558

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.208 AC: 31686 AN: 151988 Hom.: 3546 Cov.: 33 AF XY: 0.207 AC XY: 15417 AN XY: 74300

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.200

Alfa AF: 0.196 Hom.: 397

Bravo AF: 0.213

Asia WGS AF: 0.255 AC: 886 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800934; hg19: chr2-48022981; COSMIC: COSV52273967; COSMIC: COSV52273967;