rs75723219

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 103

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -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 genetic developmental and epileptic encephalopathy, developmental and epileptic encephalopathy 103.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06032279).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139137.4. 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
	KCNC2	NM_139137.4	MANE Select	c.1647G>C	p.Glu549Asp	missense	Exon 4 of 5	NP_631875.1	Q96PR1-1
	KCNC2	NM_001414192.1		c.1647G>C	p.Glu549Asp	missense	Exon 3 of 4	NP_001401121.1	Q96PR1-1
	KCNC2	NM_001260498.2		c.1647G>C	p.Glu549Asp	missense	Exon 4 of 5	NP_001247427.1	Q96PR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC2	ENST00000549446.6	TSL:1 MANE Select	c.1647G>C	p.Glu549Asp	missense	Exon 4 of 5	ENSP00000449253.2	Q96PR1-1
	KCNC2	ENST00000550433.5	TSL:1	c.1647G>C	p.Glu549Asp	missense	Exon 3 of 4	ENSP00000448301.1	Q96PR1-2
	KCNC2	ENST00000393288.2	TSL:1	c.1647G>C	p.Glu549Asp	missense	Exon 4 of 5	ENSP00000376966.2	Q96PR1-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy 103 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.060	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.28
Sift	Benign	0.80	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.40
MutPred		0.13		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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs75723219; hg19: chr12-75442066;