rs104894584

chr17-70175553-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000891.3(KCNJ2):c.514G>A(p.Asp172Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 10.0

Genes affected

KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=M2 (size 21) in uniprot entity KCNJ2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000891.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNJ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 17-70175553-G-A is Pathogenic according to our data. Variant chr17-70175553-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8927.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-70175553-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ2	NM_000891.3	c.514G>A	p.Asp172Asn	missense_variant	2/2	ENST00000243457.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ2	ENST00000243457.4	c.514G>A	p.Asp172Asn	missense_variant	2/2	1	NM_000891.3	P1
KCNJ2	ENST00000535240.1	c.514G>A	p.Asp172Asn	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2015

This variant has been reported in one family affected with short QT with tall and asymmetric T-waves (PMID: 15761194) and is not currently found in any individuals from the population databases (rs104894584, no frequency). This variant was believed to occur de novo, as all unaffected family members were negative for this variant(PMID: 15761194). Using in silico models, this variant has been predicted to cause short QT with abnormal T-wave morphology, and to increase the arrhythmia risk (PMID: 15761194, 22308236). Experimental studies have shown that this missense change reduces the channel’s sensitivity to block by internal Mg2+ cations. This leads to an increased outward current that accelerates the final phase of the cell repolarization and shortens the action potential (PMID: 8078584, 15761194,17640933, 22371365). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid with asparagine at codon 172 of the KCNJ2 protein (p.Asp172Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Short QT syndrome type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2012

- -

Short QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Short QT syndrome in the following publications (PMID:15761194;PMID:22308236). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.41	T;T
Sift4G	Benign	0.55	T;T
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.86		Loss of catalytic residue at D172 (P = 0.157);Loss of catalytic residue at D172 (P = 0.157);
MVP		0.88
MPC		1.9
ClinPred		0.90	D
GERP RS		6.0
Varity_R		0.46
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894584; hg19: chr17-68171694; COSMIC: COSV54660529;