12-75050597-G-T

Position:

• chr12-75050597-G-T

Variant summary

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

The NM_139137.4(KCNC2):​c.1408C>A​(p.Pro470Thr) 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: 31)
• Consequence: KCNC2 NM_139137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

KCNC2 (HGNC:6234): (potassium voltage-gated channel subfamily C member 2) The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

KCNC2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNC2. . Gene score misZ 2.9757 (greater than the threshold 3.09). Trascript score misZ 3.1921 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC2	NM_139137.4	c.1408C>A	p.Pro470Thr	missense_variant	3/5	ENST00000549446.6	NP_631875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC2	ENST00000549446.6	c.1408C>A	p.Pro470Thr	missense_variant	3/5	1	NM_139137.4	ENSP00000449253.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 103 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 12, 2022

ACMG classification criteria: PM2 moderated, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;L;L;L;L;L;L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.
Vest4		0.81
MutPred		0.71		Gain of glycosylation at P470 (P = 0.0296);Gain of glycosylation at P470 (P = 0.0296);Gain of glycosylation at P470 (P = 0.0296);Gain of glycosylation at P470 (P = 0.0296);Gain of glycosylation at P470 (P = 0.0296);Gain of glycosylation at P470 (P = 0.0296);Gain of glycosylation at P470 (P = 0.0296);
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.81
gMVP		0.97

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: chr12-75444377; COSMIC: COSV100129709; COSMIC: COSV100129709;