chr12-5045937-G-T

Position:

• chr12-5045937-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002234.4(KCNA5):​c.1790G>T​(p.Arg597Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R597Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4	c.1790G>T	p.Arg597Leu	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5	c.1790G>T	p.Arg597Leu	missense_variant	1/1		NM_002234.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250412 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.72	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.20	B
Vest4		0.54
MutPred		0.43		Loss of MoRF binding (P = 0.0257);
MVP		1.0
MPC		0.76
ClinPred		0.58	D
GERP RS		2.6
Varity_R		0.17
gMVP		0.28

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: rs201342234; hg19: chr12-5155103;