17-21703205-C-T

Variant names:

• chr17-21703205-C-T
• rs527236152
• NM_001194958.2:c.419C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PS1_Moderate PP3 BS2

The NM_001194958.2(KCNJ18):​c.419C>T​(p.Thr140Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,610,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000023 (0 hom.)
• 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_benign. Variant got -1 ACMG points.

• PS1: Transcript NM_001194958.2 (KCNJ18) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ18	NM_001194958.2	c.419C>T	p.Thr140Met	missense_variant	Exon 3 of 3	ENST00000567955.3	NP_001181887.2
KCNJ18	XM_005276919.4	c.725C>T	p.Thr242Met	missense_variant	Exon 2 of 2		XP_005276976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ18	ENST00000567955.3	c.419C>T	p.Thr140Met	missense_variant	Exon 3 of 3	1	NM_001194958.2	ENSP00000457807.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1457994 Hom.: 0 Cov.: 131 AF XY: 0.0000234 AC XY: 17 AN XY: 725224

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152342 Hom.: 0 Cov.: 36 AF XY: 0.0000268 AC XY: 2 AN XY: 74500

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ExAC AF: 0.0000577 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.45
MVP		0.43
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.95

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;