chr17-21415511-T-A

Position:

• chr17-21415511-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_021012.5(KCNJ12):​c.169T>A​(p.Phe57Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 71)
• Consequence: KCNJ12 NM_021012.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

Genes affected

KCNJ12 (HGNC:6258): (potassium inwardly rectifying channel subfamily J member 12) This gene encodes an inwardly rectifying K+ channel which may be blocked by divalent cations. This protein is thought to be one of multiple inwardly rectifying channels which contribute to the cardiac inward rectifier current (IK1). The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNJ12
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ12	NM_021012.5	c.169T>A	p.Phe57Ile	missense_variant	3/3	ENST00000583088.6
KCNJ12	XM_005256625.6	c.169T>A	p.Phe57Ile	missense_variant	3/3
KCNJ12	XM_011523831.3	c.169T>A	p.Phe57Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ12	ENST00000583088.6	c.169T>A	p.Phe57Ile	missense_variant	3/3	1	NM_021012.5	P1
KCNJ12	ENST00000331718.5	c.169T>A	p.Phe57Ile	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes Cov.: 71

GnomAD4 exome Cov.: 251

GnomAD4 genome Cov.: 71

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.169T>A (p.F57I) alteration is located in exon 3 (coding exon 1) of the KCNJ12 gene. This alteration results from a T to A substitution at nucleotide position 169, causing the phenylalanine (F) at amino acid position 57 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.36	T;T
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.64		Gain of MoRF binding (P = 0.11);Gain of MoRF binding (P = 0.11);
MVP		0.84
MPC		0.45
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-21318823;