rs72554071

Variant names:

• chr12-21765733-G-A
• rs72554071
• NM_004982.4:c.1265C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21765733-G-A
• chr12-21765733-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004982.4(KCNJ8):​c.1265C>T​(p.Ser422Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,842 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S422S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: KCNJ8 NM_004982.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 2.48
• Publications: 57 publications found

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]

KCNJ8 Gene-Disease associations (from GenCC):

• hypertrichotic osteochondrodysplasia Cantu type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000256615 (HGNC:58193):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040097833).
• BP6: Variant 12-21765733-G-A is Benign according to our data. Variant chr12-21765733-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 183 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004982.4. 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
	KCNJ8	NM_004982.4	MANE Select	c.1265C>T	p.Ser422Leu	missense	Exon 3 of 3	NP_004973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ8	ENST00000240662.3	TSL:1 MANE Select	c.1265C>T	p.Ser422Leu	missense	Exon 3 of 3	ENSP00000240662.2
	KCNJ8	ENST00000665145.1		c.1265C>T	p.Ser422Leu	missense	Exon 4 of 4	ENSP00000499300.1
	KCNJ8	ENST00000667884.1		c.1265C>T	p.Ser422Leu	missense	Exon 4 of 4	ENSP00000499462.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00183 AC: 461 AN: 251364 AF XY: 0.00179

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000739

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00106 AC: 1552 AN: 1461564 Hom.: 9 Cov.: 31 AF XY: 0.00112 AC XY: 814 AN XY: 727106

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000716 AC: 32 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0310 AC: 810 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86242

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000385 AC: 428 AN: 1111718

Other (OTH) AF: 0.00285 AC: 172 AN: 60384

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74464

African (AFR) AF: 0.000144 AC: 6 AN: 41548

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 114 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68034

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00188 Hom.: 6

Bravo AF: 0.00115

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNJ8: PP2, BP4, BS2

Aug 28, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23414114, 23632791, 22562657, 20558321, 22056721, 22840528, 24068186, 24667784, 19120683, 30847666)

Jul 01, 2014

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jun 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNJ8 c.1265C>T (p.Ser422Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0018 in 251364 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 293 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNJ8 causing Arrhythmia phenotype (6.3e-06). c.1265C>T has been observed in individual(s) affected with Arrhythmia, . These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia, Ventricular Fibrillation and Brugada syndrome, without strong evidence for causality (Haissaguerre_2009, Barajas-Martinez_2012, vanLint_2019). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Medeiros-Domingo_2010). The following publications have been ascertained in the context of this evaluation (PMID: 22056721, 19120683, 20558321, 30847666). ClinVar contains an entry for this variant (Variation ID: 157543). Based on the evidence outlined above, the variant was classified as likely benign.

KCNJ8-related disorder Benign:1

May 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Brugada syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy Benign:1

Jun 19, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jan 05, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.19
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.013	B
Vest4		0.10
MVP		0.43
MPC		0.93
ClinPred		0.012	T
GERP RS		4.5
Varity_R		0.069
gMVP		0.61
Mutation Taster		=79/21	polymorphism

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: rs72554071; hg19: chr12-21918667;