17-21703441-C-T

Variant names:

• chr17-21703441-C-T
• rs1469374904
• NM_001194958.2:c.655C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001194958.2(KCNJ18):​c.655C>T​(p.Arg219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 152,418 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 53)
  • Exomes 𝑓: 0.00046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0120
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• thyrotoxic periodic paralysis, susceptibility to, 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194958.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ18	NM_001194958.2	MANE Select	c.655C>T	p.Arg219Cys	missense	Exon 3 of 3	NP_001181887.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ18	ENST00000567955.3	TSL:1 MANE Select	c.655C>T	p.Arg219Cys	missense	Exon 3 of 3	ENSP00000457807.2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152300 Hom.: 0 Cov.: 53

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000955

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000465 AC: 679 AN: 1460696 Hom.: 0 Cov.: 220 AF XY: 0.000469 AC XY: 341 AN XY: 726664

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000418 AC: 14 AN: 33466

American (AMR) AF: 0.000962 AC: 43 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86218

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52484

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5766

European-Non Finnish (NFE) AF: 0.000428 AC: 476 AN: 1111868

Other (OTH) AF: 0.00126 AC: 76 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152418 Hom.: 0 Cov.: 53 AF XY: 0.000429 AC XY: 32 AN XY: 74540

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000962 AC: 4 AN: 41600

American (AMR) AF: 0.00144 AC: 22 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68050

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thyrotoxic periodic paralysis, susceptibility to, 2 Uncertain:1

Apr 24, 2017

MVZ Martinsried, Medicover Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		0.012
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.57
MVP		0.48
ClinPred		0.78	D
GERP RS		3.2
gMVP		0.76

Splicing

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

Other links and lift over

dbSNP: rs1469374904; hg19: chr17-21319309;