chr12-21773265-T-A

Variant names:

• chr12-21773265-T-A
• NM_004982.4:c.352A>T
• KCNJ8 p.Thr118Ser

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004982.4(KCNJ8):​c.352A>T​(p.Thr118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: not found (cov: 33)
• Consequence: KCNJ8 NM_004982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.971
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24075636).

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.352A>T	p.Thr118Ser	missense	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.352A>T	p.Thr118Ser	missense	Exon 2 of 3	ENSP00000240662.2	Q15842
	KCNJ8	ENST00000859815.1		c.352A>T	p.Thr118Ser	missense	Exon 2 of 4	ENSP00000529874.1
	KCNJ8	ENST00000951731.1		c.352A>T	p.Thr118Ser	missense	Exon 3 of 5	ENSP00000621790.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.97
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.28
Sift	Benign	0.076	T
Sift4G	Benign	0.19	T
Varity_R		0.079
gMVP		0.81
Mutation Taster		=97/3	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-21926199;