Genetic Variant KCNJ6:c.-27-75752A>G (chr21-37916461-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000645093.1(KCNJ6):c.-27-75752A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 149,386 control chromosomes in the GnomAD database, including 40,399 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 0.73 ( 40379 hom., cov: 27)

Exomes 𝑓: 0.51 ( 20 hom. )

Consequence

KCNJ6
ENST00000645093.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71

Publications

4 publications found

Variant links:

Genes affected

KCNJ6 (HGNC:6267): (potassium inwardly rectifying channel subfamily J member 6) This gene encodes a member of the G protein-coupled inwardly-rectifying potassium channel family of inward rectifier potassium channels. This type of potassium channel allows a greater flow of potassium into the cell than out of it. These proteins modulate many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells, through G-protein coupled receptor stimulation. Mutations in this gene are associated with Keppen-Lubinsky Syndrome, a rare condition characterized by severe developmental delay, facial dysmorphism, and intellectual disability. [provided by RefSeq, Apr 2015]

KCNJ6 Gene-Disease associations (from GenCC):

Keppen-Lubinsky syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

KCNJ6 links:

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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=-0.57).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000645093.1. 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
	KCNJ6	NM_002240.5	MANE Select	c.-605A>G		upstream_gene	N/A	NP_002231.1	P48051

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNJ6	ENST00000645093.1		c.-27-75752A>G	intron	N/A	ENSP00000493772.1	P48051
KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.-605A>G	upstream_gene	N/A	ENSP00000477437.1	P48051
KCNJ6	ENST00000917423.1		c.-1191A>G	upstream_gene	N/A	ENSP00000587482.1

Frequencies

GnomAD3 genomes

AF:

0.726

AC:

108340

AN:

149128

Hom.:

40325

Cov.:

show subpopulations

Gnomad AFR

AF:

0.903

Gnomad AMI

AF:

0.589

Gnomad AMR

AF:

0.747

Gnomad ASJ

AF:

0.660

Gnomad EAS

AF:

0.918

Gnomad SAS

AF:

0.809

Gnomad FIN

AF:

0.650

Gnomad MID

AF:

0.619

Gnomad NFE

AF:

0.611

Gnomad OTH

AF:

0.710

GnomAD4 exome

AF:

0.507

AC:

AN:

136

Hom.:

Cov.:

AF XY:

0.451

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.508

AC:

AN:

128

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.727

AC:

108456

AN:

149250

Hom.:

40379

Cov.:

AF XY:

0.730

AC XY:

53086

AN XY:

72686

show subpopulations

African (AFR)

AF:

0.903

AC:

37117

AN:

41082

American (AMR)

AF:

0.747

AC:

11153

AN:

14922

Ashkenazi Jewish (ASJ)

AF:

0.660

AC:

2254

AN:

3416

East Asian (EAS)

AF:

0.918

AC:

4629

AN:

5042

South Asian (SAS)

AF:

0.808

AC:

3765

AN:

4660

European-Finnish (FIN)

AF:

0.650

AC:

6578

AN:

10122

Middle Eastern (MID)

AF:

0.613

AC:

179

AN:

292

European-Non Finnish (NFE)

AF:

0.611

AC:

40775

AN:

66744

Other (OTH)

AF:

0.713

AC:

1471

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

1387

2773

4160

5546

6933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<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:

0.595

Hom.:

3824

Bravo

AF:

0.734

Asia WGS

AF:

0.837

AC:

2910

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.7

PromoterAI

-0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over