12-75048286-C-G

Variant names:

• chr12-75048286-C-G
• rs75723219
• NM_139137.4:c.1647G>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_139137.4(KCNC2):​c.1647G>C​(p.Glu549Asp) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC2 NM_139137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.9757 (below the threshold of 3.09). Trascript score misZ: 3.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06032279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC2	NM_139137.4	c.1647G>C	p.Glu549Asp	missense_variant	Exon 4 of 5	ENST00000549446.6	NP_631875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC2	ENST00000549446.6	c.1647G>C	p.Glu549Asp	missense_variant	Exon 4 of 5	1	NM_139137.4	ENSP00000449253.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 103 Uncertain:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.1647G>C(p.Glu549Asp) variant in KCNC2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. The amino acid Glu at position 549 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu549Asp in KCNC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Tolerated, and MutationTaster - Disease causing/Polymorphism) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Benign	0.12	.;.;T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T;.;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.060	T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	-1.6	N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.76	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.80	T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.
Vest4		0.40
MutPred		0.13		Loss of glycosylation at P551 (P = 0.0888);Loss of glycosylation at P551 (P = 0.0888);Loss of glycosylation at P551 (P = 0.0888);Loss of glycosylation at P551 (P = 0.0888);Loss of glycosylation at P551 (P = 0.0888);
MVP		0.66
MPC		0.74
ClinPred		0.039	T
GERP RS		1.7
Varity_R		0.043
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75723219; hg19: chr12-75442066;