chr11-128911314-A-T

Variant names:

• chr11-128911314-A-T
• rs1555144849
• NM_000890.5:c.41A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000890.5(KCNJ5):​c.41A>T​(p.Glu14Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.41A>T	p.Glu14Val	missense	Exon 2 of 3	NP_000881.3
	KCNJ5	NM_001354169.2		c.41A>T	p.Glu14Val	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.41A>T	p.Glu14Val	missense	Exon 2 of 3	ENSP00000433295.1	P48544
	KCNJ5	ENST00000338350.4	TSL:1	c.41A>T	p.Glu14Val	missense	Exon 3 of 4	ENSP00000339960.4	P48544
	KCNJ5	ENST00000533599.1	TSL:1	c.41A>T	p.Glu14Val	missense	Exon 1 of 2	ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.9	M
PhyloP100		8.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.066	T
Polyphen		0.78	P
Vest4		0.61
MutPred		0.39		Gain of sheet (P = 0.0061)
MVP		0.90
MPC		0.67
ClinPred		0.89	D
GERP RS		5.8
PromoterAI		0.013	Neutral
Varity_R		0.23
gMVP		0.61
Mutation Taster		=41/59	disease causing

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: rs1555144849; hg19: chr11-128781209;