chr11-128911724-G-A

Variant names:

• chr11-128911724-G-A
• rs386352319
• NM_000890.5:c.451G>A

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1 PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000890.5(KCNJ5):​c.451G>A​(p.Gly151Arg) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002633414: Functional studies suggest G151R leads to increased sodium conductance (Scholl UI et al. Proc. Natl. Acad. Sci. U.S.A. 2012" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0
• Publications: 144 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: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_000890.5 (KCNJ5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002633414: Functional studies suggest G151R leads to increased sodium conductance (Scholl UI et al. Proc. Natl. Acad. Sci. U.S.A. 2012;109:2533-8; Tauber P et al. Endocrinology. 2014;155:1353-62).
• 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 chr11-128911725-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 135679.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 11-128911724-G-A is Pathogenic according to our data. Variant chr11-128911724-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 91915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.451G>A	p.Gly151Arg	missense	Exon 2 of 3	NP_000881.3
	KCNJ5	NM_001354169.2		c.451G>A	p.Gly151Arg	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.451G>A	p.Gly151Arg	missense	Exon 2 of 3	ENSP00000433295.1	P48544
	KCNJ5	ENST00000338350.4	TSL:1	c.451G>A	p.Gly151Arg	missense	Exon 3 of 4	ENSP00000339960.4	P48544
	KCNJ5	ENST00000533599.1	TSL:1	c.451G>A	p.Gly151Arg	missense	Exon 1 of 2	ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial hyperaldosteronism type III (2)
1	-	-	Aldosterone-producing adrenal adenoma, somatic (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Loss of glycosylation at T149 (P = 0.0803)
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386352319; hg19: chr11-128781619; COSMIC: COSV57962649;