17-21702905-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001194958.2(KCNJ18):c.119G>A(p.Arg40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,531,558 control chromosomes in the GnomAD database, including 125,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12875 hom., cov: 33)
  • Exomes 𝑓: 0.43 (112702 hom.)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.37

Genes affected

KCNJ18 (HGNC:39080): (potassium inwardly rectifying channel subfamily J member 18) This gene encodes a member of the inwardly rectifying potassium channel family. Transcription of this locus is regulated by thyroid hormone, and the encoded protein plays a role in resting membrane potential maintenance. Mutations in this locus have been associated with thyrotoxic hypokalemic periodic paralysis. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060729682).
• BP6: Variant 17-21702905-G-A is Benign according to our data. Variant chr17-21702905-G-A is described in ClinVar as [Benign]. Clinvar id is 3061031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ18	NM_001194958.2	c.119G>A	p.Arg40His	missense_variant	3/3	ENST00000567955.3
KCNJ18	XM_005276919.4	c.425G>A	p.Arg142His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ18	ENST00000567955.3	c.119G>A	p.Arg40His	missense_variant	3/3	1	NM_001194958.2	P1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59236 AN: 149776 Hom.: 12868 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.429 AC: 592790 AN: 1381654 Hom.: 112702 Cov.: 73 AF XY: 0.434 AC XY: 297985 AN XY: 686120

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.829

Gnomad4 SAS exome AF: 0.564

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.433

GnomAD4 genome AF: 0.395 AC: 59256 AN: 149904 Hom.: 12875 Cov.: 33 AF XY: 0.398 AC XY: 29178 AN XY: 73222

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.788

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.419

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.417

Alfa AF: 0.407 Hom.: 1057

Bravo AF: 0.399

ESP6500AA AF: 0.142 AC: 626

ESP6500EA AF: 0.307 AC: 2643

ExAC AF: 0.350 AC: 42506

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KCNJ18-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
DEOGEN2	Benign	0.038	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
Sift	Benign	0.063	T
Sift4G	Uncertain	0.039	D
Vest4		0.18
ClinPred		0.029	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.55

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1267282483; hg19: chr17-21318773;