rs397515475
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_001378969.1(KCND3):c.680_682del(p.Phe227del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
KCND3
NM_001378969.1 inframe_deletion
NM_001378969.1 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001378969.1. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 1-111982044-CAGA-C is Pathogenic according to our data. Variant chr1-111982044-CAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 66061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCND3 | NM_001378969.1 | c.680_682del | p.Phe227del | inframe_deletion | 2/8 | ENST00000302127.5 | NP_001365898.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCND3 | ENST00000302127.5 | c.680_682del | p.Phe227del | inframe_deletion | 2/8 | 5 | NM_001378969.1 | ENSP00000306923 | P3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spinocerebellar ataxia type 19/22 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2022 | Variant summary: KCND3 c.680_682delTCT (p.Phe227del) results in an in-frame deletion that is predicted to remove one amino acid from the Ion transport domain (IPR005821) of the encoded protein. The variant was absent in 250304 control chromosomes. c.680_682delTCT has been reported in the literature to cosegregate with disease in multiple individuals from two independent well genotyped families affected with Spinocerebellar Ataxia Type 22, which overlaps with the locus of Spinocerebellar Ataxia Type 19 (example, Lee_2012). It has also been reported among pathogenic variants identified in at-least one individual within a cohort of individuals undergoing next-generation sequencing (NGS) analysis for Herediatry Ataxia's (example, Galatolo_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Lee_2012). The most pronounced variant effect results in low current densities by electrophysiological recordings and intracellular retention, suggesting that p.F227del causes a loss of channel function by interfering with proper plasma membrane targeting and incorporation into a functional tetrameric channel complex. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at