Genetic Variant KCNJ1:c.-21-2622C>T (chr11-128842886-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_153766.3(KCNJ1):c.-21-2622C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 152,168 control chromosomes in the GnomAD database, including 2,303 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2303 hom., cov: 33)

Consequence

KCNJ1
NM_153766.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0910

Publications

6 publications found

Variant links:

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

KCNJ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KCNJ1	NM_153766.3 link	c.-21-2622C>T	intron_variant	Intron 2 of 2	ENST00000392666.6	NP_722450.1	P48048-2A0A024R3K6
KCNJ1	NM_153765.3 link	c.31-2622C>T	intron_variant	Intron 2 of 2		NP_722449.3	P48048-3
KCNJ1	NM_153764.3 link	c.-21-2622C>T	intron_variant	Intron 1 of 1		NP_722448.1	P48048-2A0A024R3K6
KCNJ1	NM_153767.4 link	c.-21-2622C>T	intron_variant	Intron 3 of 3		NP_722451.1	P48048-2A0A024R3K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ1	ENST00000392666.6 link	c.-21-2622C>T		intron_variant	Intron 2 of 2	1	NM_153766.3	ENSP00000376434.1		P48048-2

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24846

AN:

152048

Hom.:

2303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.351

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.163

AC:

24851

AN:

152168

Hom.:

2303

Cov.:

AF XY:

0.167

AC XY:

12460

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.101

AC:

4194

AN:

41548

American (AMR)

AF:

0.192

AC:

2930

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

564

AN:

3470

East Asian (EAS)

AF:

0.352

AC:

1821

AN:

5176

South Asian (SAS)

AF:

0.127

AC:

615

AN:

4830

European-Finnish (FIN)

AF:

0.244

AC:

2581

AN:

10560

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.172

AC:

11684

AN:

67974

Other (OTH)

AF:

0.167

AC:

352

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1061

2123

3184

4246

5307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.167

Hom.:

8576

Bravo

AF:

0.159

Asia WGS

AF:

0.209

AC:

728

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.92

(source)

DANN

Benign

0.27

PhyloP100

-0.091

PromoterAI

-0.0098

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over