chr2-47791136-A-G

Variant names:

• chr2-47791136-A-G
• rs1800933
• NM_000179.3:c.457+13A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001406813.1(MSH6):​c.463+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,610,210 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (50 hom.)
• Consequence: MSH6 NM_001406813.1 splice_region, intron
• Clinical Significance: Likely benign reviewed by expert panel B:25
• Conservation: PhyloP100: -0.789
• Publications: 3 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-47791136-A-G is Benign according to our data. Variant chr2-47791136-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 89522.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00453 (689/151930) while in subpopulation SAS AF = 0.0108 (52/4818). AF 95% confidence interval is 0.00845. There are 2 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406813.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.457+13A>G		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.553+13A>G		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.463+7A>G		splice_region intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.457+13A>G		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.457+13A>G		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.457+13A>G		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 689 AN: 151812 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00521 AC: 1308 AN: 250876 AF XY: 0.00573

Gnomad AFR exome AF: 0.000806

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.00657

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00606 AC: 8841 AN: 1458280 Hom.: 50 Cov.: 31 AF XY: 0.00627 AC XY: 4553 AN XY: 725736

African (AFR) AF: 0.00108 AC: 36 AN: 33410

American (AMR) AF: 0.00183 AC: 82 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.0105 AC: 908 AN: 86106

European-Finnish (FIN) AF: 0.00554 AC: 296 AN: 53414

Middle Eastern (MID) AF: 0.00470 AC: 27 AN: 5750

European-Non Finnish (NFE) AF: 0.00650 AC: 7209 AN: 1108806

Other (OTH) AF: 0.00423 AC: 255 AN: 60274

GnomAD4 genome AF: 0.00453 AC: 689 AN: 151930 Hom.: 2 Cov.: 33 AF XY: 0.00439 AC XY: 326 AN XY: 74316

African (AFR) AF: 0.000946 AC: 39 AN: 41246

American (AMR) AF: 0.00295 AC: 45 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4818

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68016

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00584 Hom.: 3

Bravo AF: 0.00350

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Lynch syndrome 5 (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.75
PhyloP100		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs1800933; hg19: chr2-48018275; COSMIC: COSV104579408;