rs770087869

Variant names:

• chr12-21773264-G-A
• rs770087869
• NM_004982.4:c.353C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21773264-G-A
• chr12-21773264-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004982.4(KCNJ8):​c.353C>T​(p.Thr118Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T118A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KCNJ8 NM_004982.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.72
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2718486).
• BS2: High AC in GnomAdExome4 at 16 AD,Unknown gene.

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.353C>T	p.Thr118Ile	missense	Exon 2 of 3	NP_004973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ8	ENST00000240662.3	TSL:1 MANE Select	c.353C>T	p.Thr118Ile	missense	Exon 2 of 3	ENSP00000240662.2
	KCNJ8	ENST00000859815.1		c.353C>T	p.Thr118Ile	missense	Exon 2 of 4	ENSP00000529874.1
	KCNJ8	ENST00000951731.1		c.353C>T	p.Thr118Ile	missense	Exon 3 of 5	ENSP00000621790.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250748 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726912

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111998

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	1	-	Brugada syndrome 1 (1)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.28
Sift	Benign	0.20	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.55		Loss of disorder (P = 0.0379)
MVP		0.83
MPC		1.1
ClinPred		0.065	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.91
Mutation Taster		=87/13	polymorphism

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: rs770087869; hg19: chr12-21926198;