NM_004982.4:c.291C>G

Variant names:

• chr12-21773326-G-C
• rs34524779
• NM_004982.4:c.291C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004982.4(KCNJ8):​c.291C>G​(p.Ala97Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,614,116 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (64 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (69 hom.)
• Consequence: KCNJ8 NM_004982.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.37
• Publications: 1 publications found

Genes affected

KCNJ8 (HGNC:6269): (potassium inwardly rectifying channel subfamily J member 8) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]

KCNJ8 Gene-Disease associations (from GenCC):

• hypertrichotic osteochondrodysplasia Cantu type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNJ8-AS1 (HGNC:58193):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-21773326-G-C is Benign according to our data. Variant chr12-21773326-G-C is described in ClinVar as Benign. ClinVar VariationId is 137997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004982.4. 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
	KCNJ8	NM_004982.4	MANE Select	c.291C>G	p.Ala97Ala	synonymous	Exon 2 of 3	NP_004973.1	Q15842

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ8	ENST00000240662.3	TSL:1 MANE Select	c.291C>G	p.Ala97Ala	synonymous	Exon 2 of 3	ENSP00000240662.2	Q15842
	KCNJ8	ENST00000859815.1		c.291C>G	p.Ala97Ala	synonymous	Exon 2 of 4	ENSP00000529874.1
	KCNJ8	ENST00000951731.1		c.291C>G	p.Ala97Ala	synonymous	Exon 3 of 5	ENSP00000621790.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2552 AN: 152148 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00438 AC: 1101 AN: 251470 AF XY: 0.00302

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00173 AC: 2524 AN: 1461850 Hom.: 69 Cov.: 31 AF XY: 0.00148 AC XY: 1077 AN XY: 727224

African (AFR) AF: 0.0624 AC: 2089 AN: 33478

American (AMR) AF: 0.00264 AC: 118 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5758

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112002

Other (OTH) AF: 0.00411 AC: 248 AN: 60394

GnomAD4 genome AF: 0.0168 AC: 2554 AN: 152266 Hom.: 64 Cov.: 33 AF XY: 0.0164 AC XY: 1221 AN XY: 74462

African (AFR) AF: 0.0580 AC: 2408 AN: 41532

American (AMR) AF: 0.00732 AC: 112 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00457 Hom.: 4

Bravo AF: 0.0193

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		3.4
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34524779; hg19: chr12-21926260;