Genetic Variant KCNK15:p.Leu62Pro (chr20-44746095-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_022358.4(KCNK15):c.185T>C(p.Leu62Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L62Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNK15
NM_022358.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.69

Publications

0 publications found

Variant links:

Genes affected

KCNK15 (HGNC:13814): (potassium two pore domain channel subfamily K member 15) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity. [provided by RefSeq, Jul 2008]

KCNK15 links:

KCNK15-AS1 (HGNC:49901): (KCNK15 and WISP2 antisense RNA 1)

KCNK15-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022358.4. 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
	KCNK15	NM_022358.4	MANE Select	c.185T>C	p.Leu62Pro	missense	Exon 1 of 2	NP_071753.2	Q9H427
	KCNK15-AS1	NR_132377.1		n.133A>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNK15	ENST00000372861.5	TSL:1 MANE Select	c.185T>C	p.Leu62Pro	missense	Exon 1 of 2	ENSP00000361952.3	Q9H427
KCNK15-AS1	ENST00000445420.6	TSL:2	n.180A>G		non_coding_transcript_exon	Exon 1 of 3
KCNK15-AS1	ENST00000715845.1		n.268A>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1368336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676534

African (AFR)

AF:

0.00

AC:

AN:

28424

American (AMR)

AF:

0.00

AC:

AN:

33622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23514

East Asian (EAS)

AF:

0.00

AC:

AN:

32910

South Asian (SAS)

AF:

0.00

AC:

AN:

77366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4632

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062658

Other (OTH)

AF:

0.00

AC:

AN:

55186

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41380

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.0

PhyloP100

4.7

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Vest4

0.41

MutPred

0.70

Gain of disorder (P = 0.0198)

MVP

0.61

ClinPred

1.0

GERP RS

4.4

PromoterAI

0.036

Neutral

(source)

gMVP

0.94

Mutation Taster

=44/56

disease causing

(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

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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