rs10744676

Variant names:

• chr12-5043783-C-T
• rs10744676
• NM_002234.4:c.-365C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002234.4(KCNA5):​c.-365C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 152,100 control chromosomes in the GnomAD database, including 59,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.88 (59152 hom., cov: 32)
• Consequence: KCNA5 NM_002234.4 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-5043783-C-T is Benign according to our data. Variant chr12-5043783-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.-365C>T		upstream_gene	N/A	NP_002225.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	ENST00000252321.5	TSL:6 MANE Select	c.-365C>T		upstream_gene	N/A	ENSP00000252321.3	P22460-1

Frequencies

GnomAD3 genomes AF: 0.881 AC: 133933 AN: 151982 Hom.: 59113 Cov.: 32

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.924

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.885

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.881 AC: 134029 AN: 152100 Hom.: 59152 Cov.: 32 AF XY: 0.884 AC XY: 65700 AN XY: 74362

African (AFR) AF: 0.907 AC: 37688 AN: 41536

American (AMR) AF: 0.875 AC: 13368 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3132 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5119 AN: 5128

South Asian (SAS) AF: 0.924 AC: 4448 AN: 4814

European-Finnish (FIN) AF: 0.864 AC: 9154 AN: 10598

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58273 AN: 67950

Other (OTH) AF: 0.886 AC: 1873 AN: 2114

Alfa AF: 0.871 Hom.: 7159

Bravo AF: 0.882

Asia WGS AF: 0.956 AC: 3325 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.77
DANN	Benign	0.57
PhyloP100		-1.6
PromoterAI		0.040	Neutral

Splicing

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

Other links and lift over

dbSNP: rs10744676; hg19: chr12-5152949; COSMIC: COSV52907332;