rs16924297

chr12-21766205-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004982.4(KCNJ8):c.793T>C(p.Leu265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,110 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (21 hom.)
• Consequence: KCNJ8 NM_004982.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.671

Genes affected

KCNJ8 (HGNC:6269): (potassium inwardly rectifying channel subfamily J member 8) 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, is controlled by G-proteins. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-21766205-A-G is Benign according to our data. Variant chr12-21766205-A-G is described in ClinVar as [Benign]. Clinvar id is 221022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21766205-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.671 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00593 (903/152258) while in subpopulation AFR AF= 0.0204 (846/41548). AF 95% confidence interval is 0.0192. There are 14 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ8	NM_004982.4	c.793T>C	p.Leu265=	synonymous_variant	3/3	ENST00000240662.3
LOC105369689	XR_007063241.1	n.631+6120A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ8	ENST00000240662.3	c.793T>C	p.Leu265=	synonymous_variant	3/3	1	NM_004982.4	P1
	ENST00000542489.1	n.107-151A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152140 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

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: 0.0000588

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00150 AC: 378 AN: 251252 Hom.: 4 AF XY: 0.00105 AC XY: 143 AN XY: 135794

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000612 AC: 894 AN: 1461852 Hom.: 21 Cov.: 32 AF XY: 0.000527 AC XY: 383 AN XY: 727220

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152258 Hom.: 14 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74444

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00312 Hom.: 2

Bravo AF: 0.00698

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

SUDDEN INFANT DEATH SYNDROME Benign:1

Benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Jun 28, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	2.7
Dann	Benign	0.69

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: rs16924297; hg19: chr12-21919139;