rs772551729

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_000890.5(KCNJ5):c.658C>T(p.Arg220Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,448,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KCNJ5
NM_000890.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.95

Publications

5 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, Labcorp Genetics (formerly Invitae)
Andersen-Tawil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
long QT syndrome 13
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 2 of 3		XP_011541112.1	P48544A0A5J6E2W8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNJ5	ENST00000529694.6 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5	ENST00000338350.4 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 3 of 4	1		ENSP00000339960.4	P48544
KCNJ5	ENST00000533599.1 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 1 of 2	1		ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000820

AC:

AN:

244006

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1448014

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

718060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33122

American (AMR)

AF:

0.00

AC:

AN:

44052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25362

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.00

AC:

AN:

84476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

1103130

Other (OTH)

AF:

0.00

AC:

AN:

59714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hyperaldosteronism type III

Uncertain:1

Jan 20, 2021

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Jan 31, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has not been published in the literature and is present in population databases (noRSID, <0.001%). This sequence change replaces arginine with tryptophan at codon 220 of the KCNJ5 protein (p.Arg220Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

.;.;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H;H

PhyloP100

2.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.97

MutPred

0.95

Loss of methylation at R225 (P = 0.0504);Loss of methylation at R225 (P = 0.0504);Loss of methylation at R225 (P = 0.0504);

MVP

0.96

MPC

1.3

ClinPred

1.0

GERP RS

4.5

Varity_R

0.92

gMVP

0.96

Mutation Taster

=18/82

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over