2-47790891-A-G

Position:

chr2-47790891-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000179.3(MSH6):c.261-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,605,144 control chromosomes in the GnomAD database, including 2,371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.036 ( 131 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2240 hom. )

Consequence

MSH6
NM_000179.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 0.414

Variant links:

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]

MSH6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-47790891-A-G is Benign according to our data. Variant chr2-47790891-A-G is described in ClinVar as [Benign]. Clinvar id is 89301.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47790891-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.261-36A>G		intron_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.261-36A>G		intron_variant		1	NM_000179.3	ENSP00000234420	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0357

AC:

5432

AN:

152184

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0380

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0552

Gnomad OTH

AF:

0.0297

GnomAD3 exomes

AF:

0.0373

AC:

9344

AN:

250766

Hom.:

226

AF XY:

0.0373

AC XY:

5063

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.00906

Gnomad AMR exome

AF:

0.0338

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.0190

Gnomad SAS exome

AF:

0.0167

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0542

Gnomad OTH exome

AF:

0.0335

GnomAD4 exome

AF:

0.0518

AC:

75283

AN:

1452842

Hom.:

2240

Cov.:

AF XY:

0.0508

AC XY:

36754

AN XY:

723460

show subpopulations

Gnomad4 AFR exome

AF:

0.00786

Gnomad4 AMR exome

AF:

0.0342

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.0200

Gnomad4 SAS exome

AF:

0.0199

Gnomad4 FIN exome

AF:

0.0347

Gnomad4 NFE exome

AF:

0.0600

Gnomad4 OTH exome

AF:

0.0421

GnomAD4 genome

AF:

0.0356

AC:

5429

AN:

152302

Hom.:

131

Cov.:

AF XY:

0.0334

AC XY:

2490

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0107

Gnomad4 AMR

AF:

0.0379

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.0227

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0267

Gnomad4 NFE

AF:

0.0552

Gnomad4 OTH

AF:

0.0294

Alfa

AF:

0.0463

Hom.:

Bravo

AF:

0.0352

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lynch syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Lynch syndrome

Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over