11-30011076-C-T

Variant names:

• chr11-30011076-C-T
• rs201134414
• NM_002233.4:c.1603G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002233.4(KCNA4):​c.1603G>A​(p.Val535Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V535L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNA4 NM_002233.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• Publications: 0 publications found

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]

KCNA4 Gene-Disease associations (from GenCC):

• microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3262298).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002233.4. 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
	KCNA4	NM_002233.4	MANE Select	c.1603G>A	p.Val535Ile	missense	Exon 2 of 2	NP_002224.1	P22459

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA4	ENST00000328224.7	TSL:1 MANE Select	c.1603G>A	p.Val535Ile	missense	Exon 2 of 2	ENSP00000328511.6	P22459
	KCNA4	ENST00000953053.1		c.1603G>A	p.Val535Ile	missense	Exon 2 of 2	ENSP00000623112.1
	KCNA4	ENST00000953054.1		c.1603G>A	p.Val535Ile	missense	Exon 2 of 2	ENSP00000623113.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.0042
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.61	N
PhyloP100		4.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.14	N
REVEL	Uncertain	0.40
Sift	Benign	0.40	T
Sift4G	Benign	0.21	T
Polyphen		0.20	B
Vest4		0.35
MutPred		0.42		Gain of ubiquitination at K538 (P = 0.115)
MVP		0.62
MPC		1.2
ClinPred		0.75	D
GERP RS		4.8
Varity_R		0.096
gMVP		0.81
Mutation Taster		=85/15	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: rs201134414; hg19: chr11-30032623;