NM_033310.3:c.4C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033310.3(KCNK4):c.4C>G(p.Arg2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,544,960 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. R2H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KCNK4
NM_033310.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

1 publications found

Variant links:

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 links:

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]

KCNK4-CATSPERZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.18245369).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNK4	NM_033310.3	MANE Select	c.4C>G	p.Arg2Gly	missense	Exon 2 of 7	NP_201567.1	Q9NYG8-1
KCNK4	NM_001317090.2		c.4C>G	p.Arg2Gly	missense	Exon 2 of 7	NP_001304019.1	Q9NYG8-1
KCNK4	NR_133661.2		n.144C>G		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNK4	ENST00000422670.7	TSL:1 MANE Select	c.4C>G	p.Arg2Gly	missense	Exon 2 of 7	ENSP00000402797.2	Q9NYG8-1
KCNK4	ENST00000394525.6	TSL:1	c.4C>G	p.Arg2Gly	missense	Exon 2 of 7	ENSP00000378033.2	Q9NYG8-1
KCNK4	ENST00000539216.1	TSL:1	c.4C>G	p.Arg2Gly	missense	Exon 1 of 6	ENSP00000444948.1	Q9NYG8-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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

GnomAD2 exomes

AF:

0.00000676

AC:

AN:

147834

AF XY:

0.0000128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000919

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392600

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31330

American (AMR)

AF:

0.0000283

AC:

AN:

35334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25038

East Asian (EAS)

AF:

0.00

AC:

AN:

35502

South Asian (SAS)

AF:

0.00

AC:

AN:

78616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4644

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077244

Other (OTH)

AF:

0.00

AC:

AN:

57688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

-0.010

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

M_CAP

Benign

0.022

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.8

PhyloP100

1.9

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.14

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

0.032

Vest4

0.61

MutPred

0.45

Loss of methylation at R2 (P = 0.0244)

MVP

0.53

MPC

0.96

ClinPred

0.97

GERP RS

3.3

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.76

gMVP

0.62

Mutation Taster

=61/39

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over