11-128912117-C-G

Variant names:

• chr11-128912117-C-G
• rs7102584
• NM_000890.5:c.844C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000890.5(KCNJ5):​c.844C>G​(p.Gln282Glu) variant causes a missense change. The variant allele was found at a frequency of 0.985 in 1,613,492 control chromosomes in the GnomAD database, including 782,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q282K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.99 (74347 hom., cov: 33)
  • Exomes 𝑓: 0.98 (707837 hom.)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.89
• Publications: 47 publications found

Genes affected

KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

KCNJ5 Gene-Disease associations (from GenCC):

• familial hyperaldosteronism type III

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• Andersen-Tawil syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 13

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.373099E-7).
• BP6: Variant 11-128912117-C-G is Benign according to our data. Variant chr11-128912117-C-G is described in ClinVar as Benign. ClinVar VariationId is 137993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000890.5. 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
	KCNJ5	NM_000890.5	MANE Select	c.844C>G	p.Gln282Glu	missense	Exon 2 of 3	NP_000881.3
	KCNJ5	NM_001354169.2		c.844C>G	p.Gln282Glu	missense	Exon 3 of 4	NP_001341098.1	P48544

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ5	ENST00000529694.6	TSL:1 MANE Select	c.844C>G	p.Gln282Glu	missense	Exon 2 of 3	ENSP00000433295.1	P48544
	KCNJ5	ENST00000338350.4	TSL:1	c.844C>G	p.Gln282Glu	missense	Exon 3 of 4	ENSP00000339960.4	P48544
	KCNJ5	ENST00000533599.1	TSL:1	c.844C>G	p.Gln282Glu	missense	Exon 1 of 2	ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes AF: 0.988 AC: 150349 AN: 152158 Hom.: 74287 Cov.: 33

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.979

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.988 AC: 244884 AN: 247900 AF XY: 0.988

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.979

Gnomad OTH exome AF: 0.989

GnomAD4 exome AF: 0.984 AC: 1438219 AN: 1461216 Hom.: 707837 Cov.: 52 AF XY: 0.985 AC XY: 715780 AN XY: 726868

African (AFR) AF: 0.998 AC: 33407 AN: 33480

American (AMR) AF: 0.997 AC: 44599 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 26081 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39697 AN: 39700

South Asian (SAS) AF: 0.998 AC: 86099 AN: 86256

European-Finnish (FIN) AF: 0.977 AC: 51601 AN: 52820

Middle Eastern (MID) AF: 0.999 AC: 5765 AN: 5768

European-Non Finnish (NFE) AF: 0.981 AC: 1091323 AN: 1111950

Other (OTH) AF: 0.988 AC: 59647 AN: 60382

GnomAD4 genome AF: 0.988 AC: 150468 AN: 152276 Hom.: 74347 Cov.: 33 AF XY: 0.989 AC XY: 73610 AN XY: 74446

African (AFR) AF: 0.997 AC: 41443 AN: 41560

American (AMR) AF: 0.996 AC: 15244 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3467 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5167 AN: 5168

South Asian (SAS) AF: 0.998 AC: 4820 AN: 4830

European-Finnish (FIN) AF: 0.979 AC: 10387 AN: 10612

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.980 AC: 66636 AN: 68002

Other (OTH) AF: 0.994 AC: 2102 AN: 2114

Alfa AF: 0.982 Hom.: 18447

Bravo AF: 0.990

TwinsUK AF: 0.981 AC: 3638

ALSPAC AF: 0.981 AC: 3780

ESP6500AA AF: 0.997 AC: 4389

ESP6500EA AF: 0.982 AC: 8439

ExAC AF: 0.986 AC: 119721

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 0.984

EpiControl AF: 0.984

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Familial hyperaldosteronism type III (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	KCNJ5-related disorder (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 13 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.40
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.5	N
PhyloP100		5.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.44
ClinPred		0.0039	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.54
Mutation Taster		=97/3	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: rs7102584; hg19: chr11-128782012; COSMIC: COSV57966070;