rs2835936

Variant names:

• chr21-37753879-C-T
• rs2835936
• NM_002240.5:c.26-38748G>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.26-38748G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,148 control chromosomes in the GnomAD database, including 4,127 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 0.21 (4127 hom., cov: 32)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.26-38748G>A		intron_variant	Intron 2 of 3	ENST00000609713.2	NP_002231.1
LOC101928368	XR_244309.5	n.81-691C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.26-38748G>A		intron_variant	Intron 2 of 3	1	NM_002240.5	ENSP00000477437.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32562 AN: 152030 Hom.: 4124 Cov.: 32

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.247

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

GnomAD4 genome AF: 0.214 AC: 32565 AN: 152148 Hom.: 4127 Cov.: 32 AF XY: 0.214 AC XY: 15929 AN XY: 74390

African (AFR) AF: 0.0783 AC: 3252 AN: 41524

American (AMR) AF: 0.254 AC: 3881 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 922 AN: 3468

East Asian (EAS) AF: 0.334 AC: 1726 AN: 5170

South Asian (SAS) AF: 0.164 AC: 792 AN: 4824

European-Finnish (FIN) AF: 0.240 AC: 2538 AN: 10576

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18562 AN: 67974

Other (OTH) AF: 0.247 AC: 522 AN: 2116

Alfa AF: 0.251 Hom.: 3871

Bravo AF: 0.210

Asia WGS AF: 0.231 AC: 801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.61
PhyloP100		0.12
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: rs2835936; hg19: chr21-39126182;