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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.17
Variant links:
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]

Genome browser will be placed here

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
KCNA5NM_002234.4 linkuse as main transcriptc.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
KCNA5ENST00000252321.5 linkuse as main transcriptc.213_245del p.Asp72_Pro82del inframe_deletion 1/1 NM_002234.4 ENSP00000252321 P1P22460-1

Frequencies

GnomAD3 genomes
AF:
0.000546
AC:
83
AN:
152124
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000838
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000858
AC:
132
AN:
153812
Hom.:
0
AF XY:
0.00100
AC XY:
85
AN XY:
84636
show subpopulations
Gnomad AFR exome
AF:
0.000353
Gnomad AMR exome
AF:
0.000697
Gnomad ASJ exome
AF:
0.000244
Gnomad EAS exome
AF:
0.0000815
Gnomad SAS exome
AF:
0.00235
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000805
Gnomad OTH exome
AF:
0.000229
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000918
AC:
1284
AN:
1398538
Hom.:
1
AF XY:
0.000954
AC XY:
659
AN XY:
690980
show subpopulations
Gnomad4 AFR exome
AF:
0.000247
Gnomad4 AMR exome
AF:
0.000594
Gnomad4 ASJ exome
AF:
0.000279
Gnomad4 EAS exome
AF:
0.0000808
Gnomad4 SAS exome
AF:
0.00208
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000956
Gnomad4 OTH exome
AF:
0.000652
GnomAD4 genome
AF:
0.000545
AC:
83
AN:
152242
Hom.:
0
Cov.:
33
AF XY:
0.000457
AC XY:
34
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000838
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000384
Hom.:
0
Bravo
AF:
0.000578

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 submitterclinical testingRevvity Omics, RevvityFeb 02, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 15, 2019The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 04, 2023- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 27, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 09, 2020This variant is associated with the following publications: (PMID: 32577384, 20638934, 32397294) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144879674; hg19: chr12-5153497; API