Genetic Variant NM_001194958.2:c.1061C>T (chr17-21703847-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

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

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 6.57

Variant links:

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]

KCNJ18 links:

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ACMG classification

Classification made for transcript

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 GnomAd4 at 232 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ18	NM_001194958.2 link	c.1061C>T	p.Thr354Met	missense_variant	Exon 3 of 3	ENST00000567955.3	NP_001181887.2	B7U540
KCNJ18	XM_005276919.4 link	c.1367C>T	p.Thr456Met	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 link	c.1061C>T	p.Thr354Met	missense_variant	Exon 3 of 3	1	NM_001194958.2	ENSP00000457807.2		B7U540

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

226

AN:

152240

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

726112

show subpopulations

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.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74510

show subpopulations

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.:

Bravo

AF:

0.00161

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thyrotoxic periodic paralysis, susceptibility to, 2

Other:1

Jan 08, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.024

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.0

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.024

Vest4

0.49

MVP

0.47

ClinPred

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over