chr12-5044208-G-A

Variant names:

• chr12-5044208-G-A
• rs1862741663
• NM_002234.4:c.61G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002234.4(KCNA5):​c.61G>A​(p.Glu21Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23736092).

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.61G>A	p.Glu21Lys	missense	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.61G>A	p.Glu21Lys	missense	Exon 1 of 1	ENSP00000252321.3	P22460-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385530 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 683902

African (AFR) AF: 0.00 AC: 0 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35832

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078780

Other (OTH) AF: 0.00 AC: 0 AN: 57796

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Atrial fibrillation, familial, 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.090	D
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.26
Sift	Uncertain	0.011	D
Sift4G	Benign	0.27	T
Polyphen		0.049	B
Vest4		0.14
MutPred		0.42		Gain of MoRF binding (P = 0.0048)
MVP		1.0
MPC		0.71
ClinPred		0.40	T
GERP RS		2.7
PromoterAI		0.044	Neutral
Varity_R		0.18
gMVP		0.34
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1862741663; hg19: chr12-5153374;