NM_002234.4:c.213_245delGGACCCGGGAGTGCGGCCCTTGCCTCCGCTGCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_002234.4(KCNA5):c.213_245delGGACCCGGGAGTGCGGCCCTTGCCTCCGCTGCC(p.Asp72_Pro82del) variant causes a disruptive 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 4.17

Publications

2 publications found

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]

KCNA5 Gene-Disease associations (from GenCC):

atrial fibrillation, familial, 7
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 537316.

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA5	NM_002234.4 link	c.213_245delGGACCCGGGAGTGCGGCCCTTGCCTCCGCTGCC	p.Asp72_Pro82del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000252321.5	NP_002225.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA5	ENST00000252321.5 link	c.213_245delGGACCCGGGAGTGCGGCCCTTGCCTCCGCTGCC	p.Asp72_Pro82del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_002234.4	ENSP00000252321.3

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152124

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000858

AC:

132

AN:

153812

AF XY:

0.00100

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 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.:

AF XY:

0.000954

AC XY:

659

AN XY:

690980

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000247

AC:

AN:

32410

American (AMR)

AF:

0.000594

AC:

AN:

37056

Ashkenazi Jewish (ASJ)

AF:

0.000279

AC:

AN:

25108

East Asian (EAS)

AF:

0.0000808

AC:

AN:

37128

South Asian (SAS)

AF:

0.00208

AC:

167

AN:

80424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5238

European-Non Finnish (NFE)

AF:

0.000956

AC:

1039

AN:

1086336

Other (OTH)

AF:

0.000652

AC:

AN:

58248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.362

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000545

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41560

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000384

Hom.:

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

Sep 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32577384, 20638934, 32397294) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=52/148

disease causing (long InDel)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over