NM_002233.4:c.1285G>C

Variant names:

• chr11-30011394-C-G
• rs1850301765
• NM_002233.4:c.1285G>C

Variant summary

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

The NM_002233.4(KCNA4):​c.1285G>C​(p.Gly429Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KCNA4 NM_002233.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2428259).

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.1285G>C	p.Gly429Arg	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.1285G>C	p.Gly429Arg	missense	Exon 2 of 2	ENSP00000328511.6	P22459
	KCNA4	ENST00000953053.1		c.1285G>C	p.Gly429Arg	missense	Exon 2 of 2	ENSP00000623112.1
	KCNA4	ENST00000953054.1		c.1285G>C	p.Gly429Arg	missense	Exon 2 of 2	ENSP00000623113.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74264

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.41
Sift	Benign	0.096	T
Sift4G	Benign	0.36	T
Polyphen		0.029	B
Vest4		0.25
MutPred		0.44		Gain of solvent accessibility (P = 0.019)
MVP		0.81
MPC		0.59
ClinPred		0.47	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.59
Mutation Taster		=63/37	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: rs1850301765; hg19: chr11-30032941;