Genetic Variant KCNJ5:p.Arg319Arg (chr11-128916428-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000890.5(KCNJ5):c.957G>A(p.Arg319Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,614,198 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts 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. R319R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00065 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 6 hom. )

Consequence

KCNJ5
NM_000890.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.219

Publications

4 publications found

Variant links:

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

KCNJ5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 11-128916428-G-A is Benign according to our data. Variant chr11-128916428-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.219 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00065 (99/152334) while in subpopulation AMR AF = 0.00392 (60/15306). AF 95% confidence interval is 0.00313. There are 3 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 99 AD gene.

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.957G>A	p.Arg319Arg	synonymous	Exon 3 of 3	NP_000881.3
	KCNJ5	NM_001354169.2		c.957G>A	p.Arg319Arg	synonymous	Exon 4 of 4	NP_001341098.1	P48544

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNJ5	ENST00000529694.6	TSL:1 MANE Select	c.957G>A	p.Arg319Arg	synonymous	Exon 3 of 3	ENSP00000433295.1	P48544
KCNJ5	ENST00000338350.4	TSL:1	c.957G>A	p.Arg319Arg	synonymous	Exon 4 of 4	ENSP00000339960.4	P48544
KCNJ5	ENST00000533599.1	TSL:1	c.957G>A	p.Arg319Arg	synonymous	Exon 2 of 2	ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes

AF:

0.000650

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00105

AC:

263

AN:

251180

AF XY:

0.000994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00304

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000577

AC:

843

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

450

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00414

AC:

185

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00516

AC:

205

AN:

39700

South Asian (SAS)

AF:

0.00183

AC:

158

AN:

86258

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000193

AC:

215

AN:

1111988

Other (OTH)

AF:

0.000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000650

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41576

American (AMR)

AF:

0.00392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68034

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000505

Hom.:

Bravo

AF:

0.000899

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Familial hyperaldosteronism type III (1)

KCNJ5-related disorder (1)

Long QT syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.5

(source)

DANN

Benign

0.64

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over