chr11-128911725-G-A

Variant names:

• chr11-128911725-G-A
• rs587777437
• NM_000890.5:c.452G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000890.5(KCNJ5):​c.452G>A​(p.Gly151Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.01
• 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, 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000890.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-128911724-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 91916.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 11-128911725-G-A is Pathogenic according to our data. Variant chr11-128911725-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 135679.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.452G>A	p.Gly151Glu	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.452G>A	p.Gly151Glu	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4	c.452G>A	p.Gly151Glu	missense_variant	Exon 2 of 3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694.6	c.452G>A	p.Gly151Glu	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4	c.452G>A	p.Gly151Glu	missense_variant	Exon 3 of 4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1	c.452G>A	p.Gly151Glu	missense_variant	Exon 1 of 2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hyperaldosteronism type III Pathogenic:1

Feb 14, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Long QT syndrome Pathogenic:1

Aug 22, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to affect KCNJ5 protein function (PMID: 22203740, 22308486). This sequence change replaces glycine with glutamic acid at codon 151 of the KCNJ5 protein (p.Gly151Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hyperaldosteronism in families (PMID: 22203740, 22308486). ClinVar contains an entry for this variant (Variation ID: 135679). This variant disrupts the p.Gly151 amino acid residue in KCNJ5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22308486, 24819081). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.0	H;H;H
PhyloP100		8.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.99		Loss of catalytic residue at Y152 (P = 0.0826);Loss of catalytic residue at Y152 (P = 0.0826);Loss of catalytic residue at Y152 (P = 0.0826);
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs587777437; hg19: chr11-128781620;