rs387906778

Variant names:

• chr11-128911745-A-G
• rs387906778
• NM_000890.5:c.472A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000890.5(KCNJ5):​c.472A>G​(p.Thr158Ala) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T158R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 9.32
• Publications: 79 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 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr11-128911746-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1467663.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 11-128911745-A-G is Pathogenic according to our data. Variant chr11-128911745-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30125.Status of the report is no_assertion_criteria_provided, 0 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.472A>G	p.Thr158Ala	missense	Exon 2 of 3	NP_000881.3
	KCNJ5	NM_001354169.2		c.472A>G	p.Thr158Ala	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.472A>G	p.Thr158Ala	missense	Exon 2 of 3	ENSP00000433295.1	P48544
	KCNJ5	ENST00000338350.4	TSL:1	c.472A>G	p.Thr158Ala	missense	Exon 3 of 4	ENSP00000339960.4	P48544
	KCNJ5	ENST00000533599.1	TSL:1	c.472A>G	p.Thr158Ala	missense	Exon 1 of 2	ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Aldosterone-producing adrenal adenoma, somatic (1)
1	-	-	Familial hyperaldosteronism type III (1)
-	-	-	Andersen Tawil syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Polyphen		0.082	B
Vest4		0.95
MutPred		0.89		Loss of ubiquitination at K160 (P = 0.0821)
MVP		0.95
MPC		0.50
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.97
Mutation Taster		=1/99	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: rs387906778; hg19: chr11-128781640;