2-47808534-A-G

Variant names:

• chr2-47808534-A-G
• rs2710163
• NM_001190274.2:c.2556-107T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001190274.2(FBXO11):​c.2556-107T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 898,162 control chromosomes in the GnomAD database, including 75,298 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10590 hom., cov: 33)
  • Exomes 𝑓: 0.41 (64708 hom.)
• Consequence: FBXO11 NM_001190274.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 16 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO11	NM_001190274.2	c.2556-107T>C		intron_variant	Intron 21 of 22	ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO11	ENST00000403359.8	c.2556-107T>C		intron_variant	Intron 21 of 22	1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54182 AN: 152052 Hom.: 10590 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.405 AC: 302474 AN: 745992 Hom.: 64708 Cov.: 10 AF XY: 0.408 AC XY: 153229 AN XY: 375380

African (AFR) AF: 0.181 AC: 3270 AN: 18028

American (AMR) AF: 0.486 AC: 8287 AN: 17048

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 5509 AN: 15038

East Asian (EAS) AF: 0.637 AC: 20357 AN: 31968

South Asian (SAS) AF: 0.470 AC: 20096 AN: 42766

European-Finnish (FIN) AF: 0.341 AC: 10716 AN: 31408

Middle Eastern (MID) AF: 0.398 AC: 982 AN: 2466

European-Non Finnish (NFE) AF: 0.397 AC: 219303 AN: 552044

Other (OTH) AF: 0.396 AC: 13954 AN: 35226

GnomAD4 genome AF: 0.356 AC: 54172 AN: 152170 Hom.: 10590 Cov.: 33 AF XY: 0.359 AC XY: 26738 AN XY: 74380

African (AFR) AF: 0.200 AC: 8294 AN: 41540

American (AMR) AF: 0.454 AC: 6938 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1262 AN: 3470

East Asian (EAS) AF: 0.682 AC: 3533 AN: 5184

South Asian (SAS) AF: 0.496 AC: 2395 AN: 4828

European-Finnish (FIN) AF: 0.336 AC: 3555 AN: 10572

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26949 AN: 67972

Other (OTH) AF: 0.375 AC: 791 AN: 2112

Alfa AF: 0.386 Hom.: 13919

Bravo AF: 0.361

Asia WGS AF: 0.538 AC: 1869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.66
PhyloP100		-1.6
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)		0.16		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: rs2710163; hg19: chr2-48035673;