2-47797737-C-T

Variant names:

• chr2-47797737-C-T
• rs3136329
• NM_000179.3:c.628-874C>T

Variant summary

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

The NM_000179.3(MSH6):​c.628-874C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 157,010 control chromosomes in the GnomAD database, including 33,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33087 hom., cov: 32)
  • Exomes 𝑓: 0.61 (900 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.939

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]

RPL36AP15 (HGNC:36648): (ribosomal protein L36a pseudogene 15)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-47797737-C-T is Benign according to our data. Variant chr2-47797737-C-T is described in ClinVar as [Benign]. Clinvar id is 89544.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47797737-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.628-874C>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.628-874C>T		intron_variant	Intron 3 of 9	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98457 AN: 151936 Hom.: 33067 Cov.: 32

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.629

GnomAD4 exome AF: 0.610 AC: 3023 AN: 4956 Hom.: 900 AF XY: 0.604 AC XY: 1842 AN XY: 3048

Gnomad4 AFR exome AF: 0.817

Gnomad4 AMR exome AF: 0.605

Gnomad4 ASJ exome AF: 0.792

Gnomad4 EAS exome AF: 0.843

Gnomad4 SAS exome AF: 0.697

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.575

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.648 AC: 98517 AN: 152054 Hom.: 33087 Cov.: 32 AF XY: 0.645 AC XY: 47911 AN XY: 74324

Gnomad4 AFR AF: 0.807

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.721

Gnomad4 EAS AF: 0.865

Gnomad4 SAS AF: 0.702

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.629

Alfa AF: 0.608 Hom.: 17528

Bravo AF: 0.666

Asia WGS AF: 0.768 AC: 2672 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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% -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.43

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: rs3136329; hg19: chr2-48024876;