rs7221086

Variant names:

• chr17-70175699-C-T
• rs7221086
• NM_000891.3:c.660C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000891.3(KCNJ2):​c.660C>T​(p.Ser220Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,126 control chromosomes in the GnomAD database, including 1,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (1023 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (960 hom.)
• Consequence: KCNJ2 NM_000891.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.39
• Publications: 2 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• short QT syndrome type 3

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

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

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-70175699-C-T is Benign according to our data. Variant chr17-70175699-C-T is described in ClinVar as Benign. ClinVar VariationId is 36434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000891.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ2	NM_000891.3	MANE Select	c.660C>T	p.Ser220Ser	synonymous	Exon 2 of 2	NP_000882.1	P63252

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ2	ENST00000243457.4	TSL:1 MANE Select	c.660C>T	p.Ser220Ser	synonymous	Exon 2 of 2	ENSP00000243457.2	P63252
	KCNJ2	ENST00000535240.1	TSL:1	c.660C>T	p.Ser220Ser	synonymous	Exon 2 of 2	ENSP00000441848.1	P63252
	KCNJ2	ENST00000854891.1		c.660C>T	p.Ser220Ser	synonymous	Exon 3 of 3	ENSP00000524950.1

Frequencies

GnomAD3 genomes AF: 0.0627 AC: 9540 AN: 152116 Hom.: 1013 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: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0170 AC: 4262 AN: 251412 AF XY: 0.0122

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.00983

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00664 AC: 9714 AN: 1461892 Hom.: 960 Cov.: 32 AF XY: 0.00568 AC XY: 4131 AN XY: 727248

African (AFR) AF: 0.233 AC: 7794 AN: 33480

American (AMR) AF: 0.0120 AC: 536 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5768

European-Non Finnish (NFE) AF: 0.000323 AC: 359 AN: 1112010

Other (OTH) AF: 0.0148 AC: 894 AN: 60396

GnomAD4 genome AF: 0.0629 AC: 9579 AN: 152234 Hom.: 1023 Cov.: 32 AF XY: 0.0612 AC XY: 4554 AN XY: 74440

African (AFR) AF: 0.219 AC: 9069 AN: 41502

American (AMR) AF: 0.0225 AC: 344 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68026

Other (OTH) AF: 0.0454 AC: 96 AN: 2114

Alfa AF: 0.0312 Hom.: 323

Bravo AF: 0.0726

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Andersen Tawil syndrome (1)
-	-	1	Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 (1)
-	-	1	Atrial fibrillation, familial, 9 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Short QT syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.0
DANN	Benign	0.70
PhyloP100		3.4
Mutation Taster		=56/44	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: rs7221086; hg19: chr17-68171840;