12-5043981-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_002234.4(KCNA5):c.-167C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 691,452 control chromosomes in the GnomAD database, including 61,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15301 hom., cov: 33)
  • Exomes 𝑓: 0.40 (45941 hom.)
• Consequence: KCNA5 NM_002234.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.13).
• BP6: Variant 12-5043981-C-T is Benign according to our data. Variant chr12-5043981-C-T is described in ClinVar as [Benign]. Clinvar id is 309329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.-167C>T		5_prime_UTR_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.-167C>T		5_prime_UTR_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66650 AN: 151990 Hom.: 15282 Cov.: 33

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.404 AC: 217709 AN: 539344 Hom.: 45941 Cov.: 7 AF XY: 0.409 AC XY: 115866 AN XY: 283476

Gnomad4 AFR exome AF: 0.549

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.437

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.439 AC: 66708 AN: 152108 Hom.: 15301 Cov.: 33 AF XY: 0.444 AC XY: 33001 AN XY: 74356

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.448

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.558

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.402

Alfa AF: 0.374 Hom.: 14105

Bravo AF: 0.440

Asia WGS AF: 0.579 AC: 2009 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial fibrillation, familial, 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.13
Cadd	Benign	18
Dann	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3741930; hg19: chr12-5153147;