11-64293034-C-T

Variant names:

• chr11-64293034-C-T
• rs1364203405
• NM_033310.3:c.16C>T

Variant summary

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

The NM_033310.3(KCNK4):​c.16C>T​(p.Leu6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,018 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. L6V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNK4 NM_033310.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

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-CATSPERZ (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

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=0.35603955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033310.3. 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
	KCNK4	NM_033310.3	MANE Select	c.16C>T	p.Leu6Phe	missense	Exon 2 of 7	NP_201567.1	Q9NYG8-1
	KCNK4	NM_001317090.2		c.16C>T	p.Leu6Phe	missense	Exon 2 of 7	NP_001304019.1	Q9NYG8-1
	KCNK4	NR_133661.2		n.156C>T		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK4	ENST00000422670.7	TSL:1 MANE Select	c.16C>T	p.Leu6Phe	missense	Exon 2 of 7	ENSP00000402797.2	Q9NYG8-1
	KCNK4	ENST00000394525.6	TSL:1	c.16C>T	p.Leu6Phe	missense	Exon 2 of 7	ENSP00000378033.2	Q9NYG8-1
	KCNK4	ENST00000539216.1	TSL:1	c.16C>T	p.Leu6Phe	missense	Exon 1 of 6	ENSP00000444948.1	Q9NYG8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395018 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688014

African (AFR) AF: 0.00 AC: 0 AN: 31454

American (AMR) AF: 0.00 AC: 0 AN: 35468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 35610

South Asian (SAS) AF: 0.00 AC: 0 AN: 78800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4970

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077994

Other (OTH) AF: 0.00 AC: 0 AN: 57780

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.60		Gain of glycosylation at S3 (P = 0.1036)
MVP		0.82
MPC		0.88
ClinPred		0.92	D
GERP RS		4.3
PromoterAI		0.061	Neutral
Varity_R		0.31
gMVP		0.55
Mutation Taster		=58/42	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: rs1364203405; hg19: chr11-64060506;