12-5044239-G-T

Position:

• chr12-5044239-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002234.4(KCNA5):​c.92G>T​(p.Gly31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,539,188 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (46 hom.)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.437

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017237067).
• BP6: Variant 12-5044239-G-T is Benign according to our data. Variant chr12-5044239-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 309332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5044239-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.015 (2282/152344) while in subpopulation AFR AF= 0.0508 (2114/41588). AF 95% confidence interval is 0.049. There are 65 homozygotes in gnomad4. There are 1108 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA5	NM_002234.4	c.92G>T	p.Gly31Val	missense_variant	1/1	ENST00000252321.5	NP_002225.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA5	ENST00000252321.5	c.92G>T	p.Gly31Val	missense_variant	1/1	6	NM_002234.4	ENSP00000252321.3

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2276 AN: 152226 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00660

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00366 AC: 496 AN: 135632 Hom.: 5 AF XY: 0.00283 AC XY: 210 AN XY: 74108

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00173 AC: 2404 AN: 1386844 Hom.: 46 Cov.: 31 AF XY: 0.00152 AC XY: 1043 AN XY: 684660

Gnomad4 AFR exome AF: 0.0520

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00557

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.0150 AC: 2282 AN: 152344 Hom.: 65 Cov.: 33 AF XY: 0.0149 AC XY: 1108 AN XY: 74492

Gnomad4 AFR AF: 0.0508

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.0168

ESP6500AA AF: 0.0335 AC: 129

ESP6500EA AF: 0.000389 AC: 3

ExAC AF: 0.00261 AC: 256

Asia WGS AF: 0.00520 AC: 18 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial fibrillation, familial, 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 08, 2024

- -

Pulmonary arterial hypertension Benign:1

Benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.24
Sift	Benign	0.066	T
Sift4G	Benign	0.15	T
Polyphen		0.099	B
Vest4		0.083
MVP		0.99
MPC		0.70
ClinPred		0.0037	T
GERP RS		-0.27
Varity_R		0.10
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61737395; hg19: chr12-5153405;