Genetic Variant ENST00000645093.1: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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

KCNJ6 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=-0.57).

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5 link	c.-605A>G		upstream_gene_variant		ENST00000609713.2	NP_002231.1	P48051

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000645093.1 link	c.-27-75752A>G		intron_variant	Intron 2 of 4			ENSP00000493772.1		P48051
KCNJ6	ENST00000609713.2 link	c.-605A>G		upstream_gene_variant		1	NM_002240.5	ENSP00000477437.1		P48051

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 v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over