rs144879674
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BP6BS2
The NM_002234.4(KCNA5):c.213_245del(p.Asp72_Pro82del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000545 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00092 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
KCNA5
NM_002234.4 inframe_deletion
NM_002234.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.17
Genes affected
KCNA5 (HGNC:6224): (potassium voltage-gated channel subfamily A member 5) Potassium channels represent the most complex class of voltage-gated ino 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, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_002234.4.
BP6
Variant 12-5044331-TCGGGAGTGCGGCCCTTGCCTCCGCTGCCGGACC-T is Benign according to our data. Variant chr12-5044331-TCGGGAGTGCGGCCCTTGCCTCCGCTGCCGGACC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537316.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr12-5044331-TCGGGAGTGCGGCCCTTGCCTCCGCTGCCGGACC-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 83 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNA5 | NM_002234.4 | c.213_245del | p.Asp72_Pro82del | inframe_deletion | 1/1 | ENST00000252321.5 | NP_002225.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNA5 | ENST00000252321.5 | c.213_245del | p.Asp72_Pro82del | inframe_deletion | 1/1 | NM_002234.4 | ENSP00000252321 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000546 AC: 83AN: 152124Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000858 AC: 132AN: 153812Hom.: 0 AF XY: 0.00100 AC XY: 85AN XY: 84636
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000918 AC: 1284AN: 1398538Hom.: 1 AF XY: 0.000954 AC XY: 659AN XY: 690980
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GnomAD4 genome AF: 0.000545 AC: 83AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Atrial fibrillation, familial, 7 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 15, 2019 | The KCNA5 c.213_245del, p.Asp72_Pro82del variant (rs144879674) is reported in the literature in two probands affected with atrial fibrillation as well as three affected relatives (Yang 2010). This variant results in an in-frame deletion of 11 residues that encompass a predicted Src SH2 domain binding motif and functional analysis demonstrated that this variant reduces channel activity; however, the clinical relevance of this observation is unknown. (Yang 2010). This variant is reported in ClinVar (Variation ID: 537316) and is found in the general population with an overall allele frequency of 0.079% (147/185,166 alleles) and a South Asian allele frequency of 0.24% in the Genome Aggregation Database. Due to limited information, the clinical significance of this variant is uncertain at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2020 | This variant is associated with the following publications: (PMID: 32577384, 20638934, 32397294) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at