rs6517434

Variant names:

• chr21-37815753-C-T
• rs6517434
• NM_002240.5:c.25+24905G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002240.5(KCNJ6):​c.25+24905G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 152,232 control chromosomes in the GnomAD database, including 874 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 0.099 (874 hom., cov: 32)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.906
• Publications: 6 publications found

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)

ENSG00000292435 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.25+24905G>A		intron_variant	Intron 2 of 3	ENST00000609713.2	NP_002231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.25+24905G>A		intron_variant	Intron 2 of 3	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.25+24905G>A		intron_variant	Intron 3 of 4			ENSP00000493772.1
ENSG00000292435	ENST00000744133.1	n.181-24675C>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 15006 AN: 152114 Hom.: 872 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0631

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.0969

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

GnomAD4 genome AF: 0.0988 AC: 15040 AN: 152232 Hom.: 874 Cov.: 32 AF XY: 0.0974 AC XY: 7247 AN XY: 74428

African (AFR) AF: 0.144 AC: 5960 AN: 41524

American (AMR) AF: 0.0630 AC: 964 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4828

European-Finnish (FIN) AF: 0.105 AC: 1113 AN: 10592

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0921 AC: 6266 AN: 68012

Other (OTH) AF: 0.0959 AC: 203 AN: 2116

Alfa AF: 0.0964 Hom.: 129

Bravo AF: 0.0993

Asia WGS AF: 0.0330 AC: 117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.38
DANN	Benign	0.70
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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: rs6517434; hg19: chr21-39188056;