11-64293111-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_033310.3(KCNK4):c.93C>A(p.His31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,547,524 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 1 hom. )

Consequence

KCNK4
NM_033310.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.58

Publications

5 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018653065).

BP6

Variant 11-64293111-C-A is Benign according to our data. Variant chr11-64293111-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1392368.

BS2

High AC in GnomAd4 at 36 AD gene.

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.93C>A	p.His31Gln	missense	Exon 2 of 7	NP_201567.1	Q9NYG8-1
KCNK4	NM_001317090.2		c.93C>A	p.His31Gln	missense	Exon 2 of 7	NP_001304019.1	Q9NYG8-1
KCNK4	NR_133661.2		n.233C>A		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.93C>A	p.His31Gln	missense	Exon 2 of 7	ENSP00000402797.2	Q9NYG8-1
KCNK4	ENST00000394525.6	TSL:1	c.93C>A	p.His31Gln	missense	Exon 2 of 7	ENSP00000378033.2	Q9NYG8-1
KCNK4	ENST00000539216.1	TSL:1	c.93C>A	p.His31Gln	missense	Exon 1 of 6	ENSP00000444948.1	Q9NYG8-1

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000470

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000271

AC:

AN:

151264

AF XY:

0.000276

show subpopulations

Gnomad AFR exome

AF:

0.000234

Gnomad AMR exome

AF:

0.0000852

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000616

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.000577

AC:

805

AN:

1395176

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

382

AN XY:

688046

show subpopulations

African (AFR)

AF:

0.000254

AC:

AN:

31442

American (AMR)

AF:

0.0000568

AC:

AN:

35228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25052

East Asian (EAS)

AF:

0.00

AC:

AN:

35480

South Asian (SAS)

AF:

0.0000255

AC:

AN:

78502

European-Finnish (FIN)

AF:

0.0000411

AC:

AN:

48648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.000717

AC:

772

AN:

1077316

Other (OTH)

AF:

0.000329

AC:

AN:

57838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000236

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41584

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000458

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000271

AC:

ExAC

AF:

0.0000383

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.2

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.063

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.46

M_CAP

Benign

0.0063

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

PhyloP100

-2.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

REVEL

Benign

0.055

Sift

Benign

0.39

Sift4G

Benign

0.53

Polyphen

0.0080

Vest4

0.12

MutPred

0.28

Gain of relative solvent accessibility (P = 0.0999)

MVP

0.14

MPC

0.30

ClinPred

0.022

GERP RS

-5.5

PromoterAI

0.048

Neutral

(source)

Varity_R

0.25

gMVP

0.14

Mutation Taster

=71/29

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over