12-5043981-C-T

Variant names:

• chr12-5043981-C-T
• rs3741930
• NM_002234.4:c.-167C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 1.61
• Publications: 15 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002234.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	NM_002234.4	MANE Select	c.-167C>T		5_prime_UTR	Exon 1 of 1	NP_002225.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	ENST00000252321.5	TSL:6 MANE Select	c.-167C>T		5_prime_UTR	Exon 1 of 1	ENSP00000252321.3	P22460-1

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

African (AFR) AF: 0.549 AC: 7469 AN: 13606

American (AMR) AF: 0.431 AC: 8949 AN: 20768

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 5811 AN: 14522

East Asian (EAS) AF: 0.560 AC: 17514 AN: 31266

South Asian (SAS) AF: 0.545 AC: 26375 AN: 48376

European-Finnish (FIN) AF: 0.437 AC: 12996 AN: 29748

Middle Eastern (MID) AF: 0.381 AC: 838 AN: 2200

European-Non Finnish (NFE) AF: 0.360 AC: 125825 AN: 349794

Other (OTH) AF: 0.411 AC: 11932 AN: 29064

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

African (AFR) AF: 0.538 AC: 22338 AN: 41514

American (AMR) AF: 0.448 AC: 6859 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1421 AN: 3470

East Asian (EAS) AF: 0.617 AC: 3168 AN: 5136

South Asian (SAS) AF: 0.558 AC: 2684 AN: 4812

European-Finnish (FIN) AF: 0.438 AC: 4635 AN: 10588

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.360 AC: 24437 AN: 67974

Other (OTH) AF: 0.402 AC: 851 AN: 2116

Alfa AF: 0.378 Hom.: 18047

Bravo AF: 0.440

Asia WGS AF: 0.579 AC: 2009 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atrial fibrillation, familial, 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.96
PhyloP100		1.6
PromoterAI		-0.036	Neutral
Mutation Taster		=292/8	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3741930; hg19: chr12-5153147;