21-37625125-G-C

Variant names:

• chr21-37625125-G-C
• rs56345212
• NM_002240.5:c.*34C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.146
• 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]

ENSG00000286717 (HGNC:):

KCNJ6-AS1 (HGNC:41352): (KCNJ6 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1245230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0622 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	NM_002240.5	MANE Select	c.*34C>G		3_prime_UTR	Exon 4 of 4	NP_002231.1
	KCNJ6-AS1	NR_183540.1		n.408-73430G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.*34C>G		3_prime_UTR	Exon 4 of 4	ENSP00000477437.1
	KCNJ6	ENST00000645093.1		c.*34C>G		3_prime_UTR	Exon 5 of 5	ENSP00000493772.1
	ENSG00000286717	ENST00000667151.1		n.161-21422G>C		intron	N/A

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

GnomAD2 exomes AF: 0.0155 AC: 3586 AN: 231442 AF XY: 0.0142

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 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

African (AFR) AF: 0.0486 AC: 1401 AN: 28816

American (AMR) AF: 0.0194 AC: 822 AN: 42432

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 371 AN: 23610

East Asian (EAS) AF: 0.0526 AC: 2025 AN: 38520

South Asian (SAS) AF: 0.0194 AC: 1524 AN: 78408

European-Finnish (FIN) AF: 0.000623 AC: 32 AN: 51342

Middle Eastern (MID) AF: 0.00719 AC: 38 AN: 5282

European-Non Finnish (NFE) AF: 0.00186 AC: 1717 AN: 924346

Other (OTH) AF: 0.0115 AC: 610 AN: 53006

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

African (AFR) AF: 0.0499 AC: 2073 AN: 41558

American (AMR) AF: 0.0191 AC: 293 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.0681 AC: 353 AN: 5186

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 68022

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.42
DANN	Benign	0.51
PhyloP100		-0.15
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: rs56345212; hg19: chr21-38997427; COSMIC: COSV55722926;