11-30011660-A-G

Position:

• chr11-30011660-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002233.4(KCNA4):​c.1019T>C​(p.Met340Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KCNA4 NM_002233.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

KCNA4 (HGNC:6222): (potassium voltage-gated channel subfamily A member 4) Potassium channels represent the most complex class of voltage-gated ion 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 A-type potassium current class, the members of which may be important in the regulation of the fast repolarizing phase of action potentials in heart and thus may influence the duration of cardiac action potential.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19379428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA4	NM_002233.4	c.1019T>C	p.Met340Thr	missense_variant	2/2	ENST00000328224.7	NP_002224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA4	ENST00000328224.7	c.1019T>C	p.Met340Thr	missense_variant	2/2	1	NM_002233.4	ENSP00000328511.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2024

The c.1019T>C (p.M340T) alteration is located in exon 2 (coding exon 1) of the KCNA4 gene. This alteration results from a T to C substitution at nucleotide position 1019, causing the methionine (M) at amino acid position 340 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.48
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.073	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.29	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.28
Sift	Benign	0.54	T
Sift4G	Benign	0.54	T
Polyphen		0.0030	B
Vest4		0.27
MutPred		0.41		Loss of sheet (P = 0.0181);
MVP		0.38
MPC		0.58
ClinPred		0.065	T
GERP RS		4.3
Varity_R		0.091
gMVP		0.57

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: rs779602554; hg19: chr11-30033207; COSMIC: COSV60250980; COSMIC: COSV60250980;