2-47798555-C-T

Variant names:

• chr2-47798555-C-T
• rs1800936
• NM_000179.3:c.628-56C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000179.3(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 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -2.24
• Publications: 11 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: Benign. The variant received -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 VariationId is 89543.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.628-56C>T		intron_variant	Intron 3 of 9	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.628-56C>T		intron_variant	Intron 3 of 9	1	NM_000179.3	ENSP00000234420.5

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

African (AFR) AF: 0.107 AC: 3535 AN: 32902

American (AMR) AF: 0.0554 AC: 2445 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 1675 AN: 25958

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39454

South Asian (SAS) AF: 0.0369 AC: 3133 AN: 84924

European-Finnish (FIN) AF: 0.149 AC: 6054 AN: 40754

Middle Eastern (MID) AF: 0.0461 AC: 205 AN: 4444

European-Non Finnish (NFE) AF: 0.131 AC: 143318 AN: 1092144

Other (OTH) AF: 0.103 AC: 6092 AN: 59320

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

African (AFR) AF: 0.107 AC: 4450 AN: 41542

American (AMR) AF: 0.0799 AC: 1222 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 208 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4824

European-Finnish (FIN) AF: 0.161 AC: 1707 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8948 AN: 67998

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.119 Hom.: 2051

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

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

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
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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