2-47798555-C-T

Position:

• chr2-47798555-C-T

Variant summary

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

The ENST00000234420.11(MSH6):​c.628-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,576,304 control chromosomes in the GnomAD database, including 11,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1041 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10740 hom.)
• Consequence: MSH6 ENST00000234420.11 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -2.24

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=-0.9).
• BP6: Variant 2-47798555-C-T is Benign according to our data. Variant chr2-47798555-C-T is described in ClinVar as [Benign]. Clinvar id is 89543.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47798555-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.628-56C>T		intron_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.628-56C>T		intron_variant		1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16963 AN: 152116 Hom.: 1039 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0800

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.116

GnomAD4 exome AF: 0.117 AC: 166468 AN: 1424070 Hom.: 10740 AF XY: 0.114 AC XY: 81161 AN XY: 709974

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0554

Gnomad4 ASJ exome AF: 0.0645

Gnomad4 EAS exome AF: 0.000279

Gnomad4 SAS exome AF: 0.0369

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.111 AC: 16974 AN: 152234 Hom.: 1041 Cov.: 32 AF XY: 0.110 AC XY: 8191 AN XY: 74440

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0799

Gnomad4 ASJ AF: 0.0600

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0299

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.114

Alfa AF: 0.122 Hom.: 1574

Bravo AF: 0.106

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2018	- -

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	-0.90
CADD	Benign	0.44
DANN	Benign	0.48

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: rs1800936; hg19: chr2-48025694; COSMIC: COSV52273765; COSMIC: COSV52273765;