2-47803319-G-C

Variant names:

• chr2-47803319-G-C
• rs2072447
• NM_000179.3:c.3173-101G>C

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.3173-101G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,463,722 control chromosomes in the GnomAD database, including 414,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47361 hom., cov: 31)
  • Exomes 𝑓: 0.75 (367183 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -0.420
• Publications: 10 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=-0.91).
• BP6: Variant 2-47803319-G-C is Benign according to our data. Variant chr2-47803319-G-C is described in ClinVar as Benign. ClinVar VariationId is 89345.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3173-101G>C		intron_variant	Intron 4 of 9	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3173-101G>C		intron_variant	Intron 4 of 9	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119023 AN: 151978 Hom.: 47310 Cov.: 31

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.757

GnomAD4 exome AF: 0.747 AC: 979449 AN: 1311626 Hom.: 367183 AF XY: 0.745 AC XY: 491096 AN XY: 659336

African (AFR) AF: 0.926 AC: 27977 AN: 30202

American (AMR) AF: 0.702 AC: 29879 AN: 42592

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19109 AN: 24968

East Asian (EAS) AF: 0.875 AC: 33848 AN: 38680

South Asian (SAS) AF: 0.747 AC: 61075 AN: 81766

European-Finnish (FIN) AF: 0.663 AC: 34737 AN: 52386

Middle Eastern (MID) AF: 0.714 AC: 3844 AN: 5382

European-Non Finnish (NFE) AF: 0.742 AC: 727576 AN: 980316

Other (OTH) AF: 0.748 AC: 41404 AN: 55334

GnomAD4 genome AF: 0.783 AC: 119123 AN: 152096 Hom.: 47361 Cov.: 31 AF XY: 0.779 AC XY: 57929 AN XY: 74340

African (AFR) AF: 0.921 AC: 38273 AN: 41538

American (AMR) AF: 0.721 AC: 11012 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2663 AN: 3472

East Asian (EAS) AF: 0.879 AC: 4547 AN: 5174

South Asian (SAS) AF: 0.763 AC: 3674 AN: 4816

European-Finnish (FIN) AF: 0.650 AC: 6851 AN: 10540

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49657 AN: 67978

Other (OTH) AF: 0.754 AC: 1590 AN: 2108

Alfa AF: 0.756 Hom.: 5498

Bravo AF: 0.796

Asia WGS AF: 0.821 AC: 2858 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.91
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2072447; hg19: chr2-48030458;