21-38299682-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_170736.3(KCNJ15):c.421C>T(p.His141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,884 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (2 hom.)
• Consequence: KCNJ15 NM_170736.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

Genes affected

KCNJ15 (HGNC:6261): (potassium inwardly rectifying channel subfamily J member 15) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Eight transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21215871).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ15	NM_170736.3	c.421C>T	p.His141Tyr	missense_variant	3/3	ENST00000398938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ15	ENST00000398938.7	c.421C>T	p.His141Tyr	missense_variant	3/3	1	NM_170736.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251368 Hom.: 2 AF XY: 0.0000589 AC XY: 8 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461884 Hom.: 2 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.421C>T (p.H141Y) alteration is located in exon 3 (coding exon 1) of the KCNJ15 gene. This alteration results from a C to T substitution at nucleotide position 421, causing the histidine (H) at amino acid position 141 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	19
Dann	Benign	0.75
DEOGEN2	Benign	0.21	T;T;T;T;T;T;.;T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.5	L;L;.;L;L;L;.;L;L;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0090	B;B;.;B;B;B;.;B;B;.
Vest4		0.48
MutPred		0.43		Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);Gain of stability (P = 0.1689);
MVP		0.77
MPC		0.83
ClinPred		0.069	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs758828176; hg19: chr21-39671604; COSMIC: COSV60810940; COSMIC: COSV60810940;