rs527236156

Positions:

• chr17-21703981-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001194958.2(KCNJ18):​c.1195C>T​(p.Arg399*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,601,800 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0092 (25 hom., cov: 35)
  • Exomes 𝑓: 0.00097 (33 hom.)
• Consequence: KCNJ18 NM_001194958.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00916 (1395/152302) while in subpopulation AFR AF= 0.0321 (1334/41556). AF 95% confidence interval is 0.0307. There are 25 homozygotes in gnomad4. There are 626 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ18	NM_001194958.2	c.1195C>T	p.Arg399*	stop_gained	3/3	ENST00000567955.3	NP_001181887.2
KCNJ18	XM_005276919.4	c.1501C>T	p.Arg501*	stop_gained	2/2		XP_005276976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ18	ENST00000567955.3	c.1195C>T	p.Arg399*	stop_gained	3/3	1	NM_001194958.2	ENSP00000457807.2

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1388 AN: 152184 Hom.: 25 Cov.: 35

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000971 AC: 1408 AN: 1449498 Hom.: 33 Cov.: 35 AF XY: 0.000859 AC XY: 619 AN XY: 720188

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000786

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00916 AC: 1395 AN: 152302 Hom.: 25 Cov.: 35 AF XY: 0.00841 AC XY: 626 AN XY: 74458

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00740 Hom.: 0

Bravo AF: 0.00997

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00228 AC: 277

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
Eigen	Benign	-0.0031
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.066	N
Vest4		0.068
GERP RS		0.58

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs527236156; hg19: chr17-21319849;