17-70174715-A-G

Variant names:

• chr17-70174715-A-G
• rs10083866
• NM_000891.3:c.-216-109A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000891.3(KCNJ2):​c.-216-109A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 370,352 control chromosomes in the GnomAD database, including 1,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.063 (1020 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (180 hom.)
• Consequence: KCNJ2 NM_000891.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07
• Publications: 0 publications found

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]

KCNJ2 Gene-Disease associations (from GenCC):

• Andersen-Tawil syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• short QT syndrome type 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• long QT syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-70174715-A-G is Benign according to our data. Variant chr17-70174715-A-G is described in ClinVar as [Benign]. Clinvar id is 1268619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.-216-109A>G		intron_variant	Intron 1 of 1	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4	c.-216-109A>G		intron_variant	Intron 1 of 1	1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1	c.-216-109A>G		intron_variant	Intron 1 of 1	1		ENSP00000441848.1

Frequencies

GnomAD3 genomes AF: 0.0627 AC: 9545 AN: 152210 Hom.: 1010 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.0458

GnomAD4 exome AF: 0.00924 AC: 2015 AN: 218024 Hom.: 180 AF XY: 0.00748 AC XY: 866 AN XY: 115758

African (AFR) AF: 0.223 AC: 1602 AN: 7168

American (AMR) AF: 0.0140 AC: 152 AN: 10872

Ashkenazi Jewish (ASJ) AF: 0.000320 AC: 2 AN: 6256

East Asian (EAS) AF: 0.00 AC: 0 AN: 11948

South Asian (SAS) AF: 0.000471 AC: 15 AN: 31828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9690

Middle Eastern (MID) AF: 0.0167 AC: 14 AN: 840

European-Non Finnish (NFE) AF: 0.000439 AC: 56 AN: 127592

Other (OTH) AF: 0.0147 AC: 174 AN: 11830

GnomAD4 genome AF: 0.0629 AC: 9584 AN: 152328 Hom.: 1020 Cov.: 32 AF XY: 0.0611 AC XY: 4553 AN XY: 74488

African (AFR) AF: 0.218 AC: 9075 AN: 41544

American (AMR) AF: 0.0225 AC: 345 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000852 AC: 58 AN: 68040

Other (OTH) AF: 0.0454 AC: 96 AN: 2116

Alfa AF: 0.0588 Hom.: 113

Bravo AF: 0.0726

Asia WGS AF: 0.0130 AC: 45 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.016
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10083866; hg19: chr17-68170856;