21-37625125-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002240.5(KCNJ6):c.*34C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,398,072 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (70 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (145 hom.)
• Consequence: KCNJ6 NM_002240.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.146

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-37625125-G-C is Benign according to our data. Variant chr21-37625125-G-C is described in ClinVar as [Benign]. Clinvar id is 1245230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ6	NM_002240.5	c.*34C>G		3_prime_UTR_variant	4/4	ENST00000609713.2
KCNJ6-AS1	NR_183540.1	n.408-73430G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ6	ENST00000609713.2	c.*34C>G		3_prime_UTR_variant	4/4	1	NM_002240.5	P1
	ENST00000667151.1	n.161-21422G>C		intron_variant, non_coding_transcript_variant
KCNJ6	ENST00000645093.1	c.*34C>G		3_prime_UTR_variant	5/5			P1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3032 AN: 152192 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.0681

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0155 AC: 3586 AN: 231442 Hom.: 73 AF XY: 0.0142 AC XY: 1778 AN XY: 125156

Gnomad AFR exome AF: 0.0502

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0690

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.000453

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.00686 AC: 8540 AN: 1245762 Hom.: 145 Cov.: 17 AF XY: 0.00703 AC XY: 4409 AN XY: 626792

Gnomad4 AFR exome AF: 0.0486

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.0526

Gnomad4 SAS exome AF: 0.0194

Gnomad4 FIN exome AF: 0.000623

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0200 AC: 3045 AN: 152310 Hom.: 70 Cov.: 33 AF XY: 0.0194 AC XY: 1446 AN XY: 74478

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.0681

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.00326 Hom.: 1

Bravo AF: 0.0231

Asia WGS AF: 0.0590 AC: 204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.42
Dann	Benign	0.51

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: rs56345212; hg19: chr21-38997427; COSMIC: COSV55722926;