chr20-44750605-C-T

Variant names:

• chr20-44750605-C-T
• rs369120126
• NM_022358.4:c.760C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022358.4(KCNK15):​c.760C>T​(p.Pro254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000998 in 1,603,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. P254A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KCNK15 NM_022358.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042822212).

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.760C>T	p.Pro254Ser	missense	Exon 2 of 2	NP_071753.2	Q9H427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK15	ENST00000372861.5	TSL:1 MANE Select	c.760C>T	p.Pro254Ser	missense	Exon 2 of 2	ENSP00000361952.3	Q9H427

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000172 AC: 4 AN: 233142 AF XY: 0.0000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1451408 Hom.: 0 Cov.: 39 AF XY: 0.0000125 AC XY: 9 AN XY: 722406

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.0000224 AC: 1 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111038

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74206

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.81
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.23
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.026
Sift	Benign	0.16	T
Sift4G	Benign	0.32	T
Vest4		0.036
MutPred		0.33		Gain of phosphorylation at P254 (P = 0.0245)
MVP		0.14
ClinPred		0.029	T
GERP RS		-0.14
gMVP		0.31
Mutation Taster		=96/4	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: rs369120126; hg19: chr20-43379246;