2-47803699-A-T

Variant names:

• chr2-47803699-A-T
• rs2020911
• NM_000179.3:c.3438+14A>T

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.3438+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,612,944 control chromosomes in the GnomAD database, including 125,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9378 hom., cov: 32)
  • Exomes 𝑓: 0.39 (116097 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: -0.0370
• Publications: 34 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=-0.82).
• BP6: Variant 2-47803699-A-T is Benign according to our data. Variant chr2-47803699-A-T is described in ClinVar as Benign. ClinVar VariationId is 42471.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.601 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3438+14A>T		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.3534+14A>T		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3444+14A>T		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.3438+14A>T		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*2785+14A>T		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.3465+14A>T		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50795 AN: 151926 Hom.: 9379 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.412 AC: 103194 AN: 250622 AF XY: 0.413

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.508

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.624

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.394 AC: 575178 AN: 1460902 Hom.: 116097 Cov.: 37 AF XY: 0.396 AC XY: 287563 AN XY: 726788

African (AFR) AF: 0.158 AC: 5292 AN: 33466

American (AMR) AF: 0.497 AC: 22240 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9575 AN: 26126

East Asian (EAS) AF: 0.568 AC: 22512 AN: 39648

South Asian (SAS) AF: 0.472 AC: 40699 AN: 86234

European-Finnish (FIN) AF: 0.339 AC: 18105 AN: 53412

Middle Eastern (MID) AF: 0.379 AC: 2185 AN: 5764

European-Non Finnish (NFE) AF: 0.388 AC: 431473 AN: 1111260

Other (OTH) AF: 0.383 AC: 23097 AN: 60288

GnomAD4 genome AF: 0.334 AC: 50784 AN: 152042 Hom.: 9378 Cov.: 32 AF XY: 0.339 AC XY: 25189 AN XY: 74318

African (AFR) AF: 0.175 AC: 7251 AN: 41478

American (AMR) AF: 0.435 AC: 6646 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1244 AN: 3464

East Asian (EAS) AF: 0.619 AC: 3191 AN: 5158

South Asian (SAS) AF: 0.492 AC: 2372 AN: 4818

European-Finnish (FIN) AF: 0.330 AC: 3487 AN: 10572

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.374 AC: 25410 AN: 67954

Other (OTH) AF: 0.348 AC: 736 AN: 2114

Alfa AF: 0.338 Hom.: 1154

Bravo AF: 0.337

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	Lynch syndrome 5 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (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	-0.82
CADD	Benign	4.0
DANN	Benign	0.63
PhyloP100		-0.037
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: rs2020911; hg19: chr2-48030838; COSMIC: COSV52273834; COSMIC: COSV52273834;