2-47803418-A-T

Variant names:

• chr2-47803418-A-T
• rs1553331242
• NM_000179.3:c.3173-2A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000179.3(MSH6):​c.3173-2A>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.28
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.4, offset of 28, new splice context is: ctgtgcctggctaactatAGtcg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47803418-A-T is Pathogenic according to our data. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47803418-A-T is described in CliVar as Pathogenic. Clinvar id is 489178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3173-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 9	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3173-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 9	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 01, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		7.3
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553331242; hg19: chr2-48030557;