11-64293122-C-T

Variant names:

• chr11-64293122-C-T
• rs1318097813
• NM_033310.3:c.104C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033310.3(KCNK4):​c.104C>T​(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNK4 NM_033310.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850

Genes affected

KCNK4 (HGNC:6279): (potassium two pore domain channel subfamily K member 4) This gene encodes a member of the TWIK-related arachidonic acid-stimulated two pore potassium channel subfamily. The encoded protein homodimerizes and functions as an outwardly rectifying channel. This channel is regulated by polyunsaturated fatty acids, temperature and mechanical deformation of the lipid membrane. This protein is expressed primarily in neural tissues and may be involved in regulating the noxious input threshold in dorsal root ganglia neurons. Alternate splicing results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream testis expressed 40 (TEX40) gene, as represented in GeneID: 106780802. [provided by RefSeq, Nov 2015]

KCNK4-TEX40 (HGNC:56753): (KCNK4-CATSPERZ readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring KCNK4 (potassium channel subfamily K member 4) and the downstream TEX40 (testis expressed 40) chromosome 11. The readthrough transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046903223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK4	NM_033310.3	c.104C>T	p.Ala35Val	missense_variant	Exon 2 of 7	ENST00000422670.7	NP_201567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK4	ENST00000422670.7	c.104C>T	p.Ala35Val	missense_variant	Exon 2 of 7	1	NM_033310.3	ENSP00000402797.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393352 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 687058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with KCNK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1432584). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine with valine at codon 35 of the KCNK4 protein (p.Ala35Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.68	.;.;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.10
MutPred		0.34		Loss of disorder (P = 0.1546);Loss of disorder (P = 0.1546);Loss of disorder (P = 0.1546);
MVP		0.63
MPC		0.23
ClinPred		0.10	T
GERP RS		1.2
Varity_R		0.15
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1318097813; hg19: chr11-64060594;