17-21704005-C-T

Position:

• chr17-21704005-C-T

Variant summary

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

The NM_001194958.2(KCNJ18):​c.1219C>T​(p.Gln407Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00263 in 1,594,896 control chromosomes in the GnomAD database, including 48 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 0.0075 (14 hom., cov: 35)
  • Exomes 𝑓: 0.0021 (34 hom.)
• Consequence: KCNJ18 NM_001194958.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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 = 0.00748 (1140/152342) while in subpopulation AFR AF= 0.0186 (774/41578). AF 95% confidence interval is 0.0175. There are 14 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ18	NM_001194958.2	c.1219C>T	p.Gln407Ter	stop_gained	3/3	ENST00000567955.3	NP_001181887.2
KCNJ18	XM_005276919.4	c.1525C>T	p.Gln509Ter	stop_gained	2/2		XP_005276976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ18	ENST00000567955.3	c.1219C>T	p.Gln407Ter	stop_gained	3/3	1	NM_001194958.2	ENSP00000457807	P1

Frequencies

GnomAD3 genomes AF: 0.00746 AC: 1136 AN: 152224 Hom.: 14 Cov.: 35

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.00212 AC: 3052 AN: 1442554 Hom.: 34 Cov.: 35 AF XY: 0.00203 AC XY: 1454 AN XY: 715752

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00774

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.0000625

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.00748 AC: 1140 AN: 152342 Hom.: 14 Cov.: 35 AF XY: 0.00766 AC XY: 571 AN XY: 74496

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00534 Hom.: 1

Bravo AF: 0.00878

ExAC AF: 0.00267 AC: 324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D
Vest4		0.052
GERP RS		3.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs527236157; hg19: chr17-21319873;