2-47806412-C-G

Variant names:

• chr2-47806412-C-G
• rs3136367
• NM_000179.3:c.3802-40C>G

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.3802-40C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,613,664 control chromosomes in the GnomAD database, including 445,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46154 hom., cov: 32)
  • Exomes 𝑓: 0.74 (399652 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: -1.00
• Publications: 22 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=-0.83).
• BP6: Variant 2-47806412-C-G is Benign according to our data. Variant chr2-47806412-C-G is described in ClinVar as Benign. ClinVar VariationId is 36594.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3802-40C>G		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.3898-40C>G		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3808-40C>G		intron	N/A	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.3802-40C>G		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*3149-40C>G		intron	N/A	ENSP00000405294.1
	FBXO11	ENST00000682451.1		n.4336G>C		non_coding_transcript_exon	Exon 23 of 23

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117396 AN: 151974 Hom.: 46108 Cov.: 32

Gnomad AFR AF: 0.915

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.745

GnomAD2 exomes AF: 0.734 AC: 184101 AN: 250824 AF XY: 0.733

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.883

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.730

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.738 AC: 1078548 AN: 1461572 Hom.: 399652 Cov.: 45 AF XY: 0.736 AC XY: 535403 AN XY: 727108

African (AFR) AF: 0.917 AC: 30707 AN: 33476

American (AMR) AF: 0.622 AC: 27803 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 19938 AN: 26128

East Asian (EAS) AF: 0.872 AC: 34585 AN: 39680

South Asian (SAS) AF: 0.739 AC: 63727 AN: 86254

European-Finnish (FIN) AF: 0.665 AC: 35482 AN: 53394

Middle Eastern (MID) AF: 0.706 AC: 4075 AN: 5768

European-Non Finnish (NFE) AF: 0.735 AC: 817551 AN: 1111784

Other (OTH) AF: 0.740 AC: 44680 AN: 60388

GnomAD4 genome AF: 0.772 AC: 117488 AN: 152092 Hom.: 46154 Cov.: 32 AF XY: 0.767 AC XY: 57039 AN XY: 74322

African (AFR) AF: 0.915 AC: 37992 AN: 41524

American (AMR) AF: 0.660 AC: 10075 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2648 AN: 3470

East Asian (EAS) AF: 0.875 AC: 4527 AN: 5174

South Asian (SAS) AF: 0.755 AC: 3640 AN: 4824

European-Finnish (FIN) AF: 0.653 AC: 6875 AN: 10536

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49308 AN: 67982

Other (OTH) AF: 0.741 AC: 1563 AN: 2108

Alfa AF: 0.700 Hom.: 4302

Bravo AF: 0.780

Asia WGS AF: 0.807 AC: 2810 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported.

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

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 Uncertain:1 Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Lynch syndrome 5 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1%

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.42
DANN	Benign	0.57
PhyloP100		-1.0
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: rs3136367; hg19: chr2-48033551; COSMIC: COSV52273637; COSMIC: COSV52273637;