chr2-47795842-G-T

Variant names:

• chr2-47795842-G-T
• rs1800934
• NM_000179.3:c.458-52G>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.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
• Publications: 13 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=-0.89).
• BP6: Variant 2-47795842-G-T is Benign according to our data. Variant chr2-47795842-G-T is described in ClinVar as Benign. ClinVar VariationId is 89532.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.458-52G>T		intron_variant	Intron 2 of 9	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.458-52G>T		intron_variant	Intron 2 of 9	1	NM_000179.3	ENSP00000234420.5

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

African (AFR) AF: 0.298 AC: 9251 AN: 31056

American (AMR) AF: 0.115 AC: 4893 AN: 42648

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7234 AN: 25400

East Asian (EAS) AF: 0.284 AC: 10742 AN: 37790

South Asian (SAS) AF: 0.210 AC: 17349 AN: 82682

European-Finnish (FIN) AF: 0.123 AC: 6451 AN: 52404

Middle Eastern (MID) AF: 0.250 AC: 1385 AN: 5538

European-Non Finnish (NFE) AF: 0.171 AC: 177772 AN: 1040386

Other (OTH) AF: 0.199 AC: 11422 AN: 57384

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

African (AFR) AF: 0.294 AC: 12174 AN: 41414

American (AMR) AF: 0.157 AC: 2392 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1015 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1299 AN: 5178

South Asian (SAS) AF: 0.205 AC: 989 AN: 4820

European-Finnish (FIN) AF: 0.119 AC: 1263 AN: 10578

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11839 AN: 67952

Other (OTH) AF: 0.200 AC: 422 AN: 2110

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

-

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	-0.89
CADD	Benign	2.6
DANN	Benign	0.50
PhyloP100		0.38
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: rs1800934; hg19: chr2-48022981; COSMIC: COSV52273967;