rs527236152

Positions:

• chr17-21703205-C-A
• chr17-21703205-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001194958.2(KCNJ18):​c.419C>A​(p.Thr140Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 9/15 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T140M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 36)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ18	NM_001194958.2	c.419C>A	p.Thr140Lys	missense_variant	3/3	ENST00000567955.3	NP_001181887.2
KCNJ18	XM_005276919.4	c.725C>A	p.Thr242Lys	missense_variant	2/2		XP_005276976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ18	ENST00000567955.3	c.419C>A	p.Thr140Lys	missense_variant	3/3	1	NM_001194958.2	ENSP00000457807.2

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 131

GnomAD4 genome Cov.: 36

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.72
MutPred		0.87		Gain of ubiquitination at T140 (P = 0.0247);
MVP		0.46
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs527236152; hg19: chr17-21319073;