21-38300210-C-G

Position:

• chr21-38300210-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170736.3(KCNJ15):​c.949C>G​(p.Leu317Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: KCNJ15 NM_170736.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22367215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ15	NM_170736.3	c.949C>G	p.Leu317Val	missense_variant	3/3	ENST00000398938.7	NP_733932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ15	ENST00000398938.7	c.949C>G	p.Leu317Val	missense_variant	3/3	1	NM_170736.3	ENSP00000381911	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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

Dec 20, 2023

The c.949C>G (p.L317V) alteration is located in exon 3 (coding exon 1) of the KCNJ15 gene. This alteration results from a C to G substitution at nucleotide position 949, causing the leucine (L) at amino acid position 317 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T;T;T;T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	.;T;.;.;.;.;.
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.073	D
MutationAssessor	Benign	2.0	M;M;M;M;M;M;M
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.57	.;.;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.20	.;.;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T
Polyphen		0.34	B;B;B;B;B;B;B
Vest4		0.23
MutPred		0.36		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.81
MPC		0.57
ClinPred		0.59	D
GERP RS		5.8
Varity_R		0.28
gMVP		0.43

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: rs930728785; hg19: chr21-39672132;