rs748305494

Variant names:

• chr11-128839210-T-A
• rs748305494
• NM_153766.3:c.1034A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-128839210-T-A
• chr11-128839210-T-C
• chr11-128839210-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000392666.6(KCNJ1):​c.1034A>T​(p.Asp345Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D345G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ1 ENST00000392666.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.85
• Publications: 0 publications found

Genes affected

KCNJ1 (HGNC:6255): (potassium inwardly rectifying channel subfamily J member 1) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. It is activated by internal ATP and probably plays an important role in potassium homeostasis. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Mutations in this gene have been associated with antenatal Bartter syndrome, which is characterized by salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNJ1 Gene-Disease associations (from GenCC):

• Bartter disease type 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• antenatal Bartter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -0.27693 (below the threshold of 3.09). Trascript score misZ: 0.38698 (below the threshold of 3.09). GenCC associations: The gene is linked to antenatal Bartter syndrome, Bartter disease type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34946686).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000392666.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ1	NM_153766.3	MANE Select	c.1034A>T	p.Asp345Val	missense	Exon 3 of 3	NP_722450.1
	KCNJ1	NM_000220.6		c.1091A>T	p.Asp364Val	missense	Exon 2 of 2	NP_000211.1
	KCNJ1	NM_153765.3		c.1085A>T	p.Asp362Val	missense	Exon 3 of 3	NP_722449.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ1	ENST00000392666.6	TSL:1 MANE Select	c.1034A>T	p.Asp345Val	missense	Exon 3 of 3	ENSP00000376434.1
	KCNJ1	ENST00000392664.2	TSL:1	c.1091A>T	p.Asp364Val	missense	Exon 2 of 2	ENSP00000376432.2
	KCNJ1	ENST00000324036.7	TSL:1	c.1034A>T	p.Asp345Val	missense	Exon 4 of 4	ENSP00000316233.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.57
Sift	Benign	0.089	T
Sift4G	Benign	0.19	T
Polyphen		0.92	P
Vest4		0.25
MutPred		0.48		Gain of helix (P = 0.0117)
MVP		0.87
MPC		0.26
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.73
Mutation Taster		=50/50

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: rs748305494; hg19: chr11-128709105;