NM_002240.5:c.-28+3550G>A

Variant names:

• chr21-37912334-C-T
• rs2836049
• NM_002240.5:c.-28+3550G>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.-28+3550G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 152,122 control chromosomes in the GnomAD database, including 450 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 0.074 (450 hom., cov: 33)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 2 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: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

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 (NFE) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002240.5. 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.-28+3550G>A		intron	N/A	NP_002231.1	P48051

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.-28+3550G>A		intron	N/A	ENSP00000477437.1	P48051
	KCNJ6	ENST00000645093.1		c.-27-71625G>A		intron	N/A	ENSP00000493772.1	P48051
	KCNJ6	ENST00000917423.1		c.-28+895G>A		intron	N/A	ENSP00000587482.1

Frequencies

GnomAD3 genomes AF: 0.0739 AC: 11232 AN: 152004 Hom.: 450 Cov.: 33

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.0480

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0796

Gnomad OTH AF: 0.0642

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

GnomAD4 genome AF: 0.0740 AC: 11258 AN: 152122 Hom.: 450 Cov.: 33 AF XY: 0.0735 AC XY: 5467 AN XY: 74350

African (AFR) AF: 0.0789 AC: 3275 AN: 41520

American (AMR) AF: 0.0530 AC: 811 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.0481 AC: 249 AN: 5174

South Asian (SAS) AF: 0.0532 AC: 256 AN: 4814

European-Finnish (FIN) AF: 0.0896 AC: 946 AN: 10562

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0796 AC: 5409 AN: 67970

Other (OTH) AF: 0.0640 AC: 135 AN: 2110

Alfa AF: 0.0745 Hom.: 137

Bravo AF: 0.0720

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.69
PhyloP100		0.058
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: rs2836049; hg19: chr21-39284637;