21-37625563-G-A

Position:

• chr21-37625563-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002240.5(KCNJ6):​c.947-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,037,710 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (81 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (55 hom.)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.446

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]

ENSG00000286717 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-37625563-G-A is Benign according to our data. Variant chr21-37625563-G-A is described in ClinVar as [Benign]. Clinvar id is 1283542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.947-79C>T		intron_variant		ENST00000609713.2	NP_002231.1
KCNJ6-AS1	NR_183540.1	n.408-72992G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.947-79C>T		intron_variant		1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.947-79C>T		intron_variant				ENSP00000493772.1
ENSG00000286717	ENST00000667151.1	n.161-20984G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2659 AN: 152192 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00226 AC: 2001 AN: 885400 Hom.: 55 AF XY: 0.00199 AC XY: 898 AN XY: 451344

Gnomad4 AFR exome AF: 0.0625

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.00600

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000981

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.00476

GnomAD4 genome AF: 0.0175 AC: 2666 AN: 152310 Hom.: 81 Cov.: 33 AF XY: 0.0165 AC XY: 1232 AN XY: 74494

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0171 Hom.: 6

Bravo AF: 0.0203

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs7281640; hg19: chr21-38997865;