17-21703847-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001194958.2(KCNJ18):c.1061C>T(p.Thr354Met) variant causes a missense change. The variant allele was found at a frequency of 0.00029 in 1,611,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 6.57

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a mutagenesis_site Decreases the single-channel open probability (Po) without altering its conductance. (size 0) in uniprot entity KCJ18_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.023779243).
• BS2: High AC in GnomAd at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ18	NM_001194958.2	c.1061C>T	p.Thr354Met	missense_variant	3/3	ENST00000567955.3
KCNJ18	XM_005276919.4	c.1367C>T	p.Thr456Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ18	ENST00000567955.3	c.1061C>T	p.Thr354Met	missense_variant	3/3	1	NM_001194958.2	P1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152240 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1459612 Hom.: 0 Cov.: 35 AF XY: 0.000128 AC XY: 93 AN XY: 726112

Gnomad4 AFR exome AF: 0.00465

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152358 Hom.: 0 Cov.: 35 AF XY: 0.00161 AC XY: 120 AN XY: 74510

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000674 Hom.: 0

Bravo AF: 0.00161

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Thyrotoxic periodic paralysis, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 08, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	27
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.024	T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Vest4		0.49
MVP		0.47
ClinPred		0.18	T
GERP RS		5.7
Varity_R		0.58
gMVP		0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs527236158; hg19: chr17-21319715;