12-75042374-T-C

Variant names:

• chr12-75042374-T-C
• rs201339164
• ENST00000548513.5:c.1781A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_139136.4(KCNC2):​c.1781A>G​(p.Asp594Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,459,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D594V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNC2 NM_139136.4 missense, splice_region
• Scores: Splicing: ADA: 0.006763
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.27
• 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

ENSG00000257434 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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: 2.997 (below the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 103, genetic developmental and epileptic encephalopathy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139136.4. 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.*731A>G		3_prime_UTR	Exon 5 of 5	NP_631875.1	Q96PR1-1
	KCNC2	NM_001414195.1		c.1781A>G	p.Asp594Gly	missense splice_region	Exon 4 of 5	NP_001401124.1	Q96PR1-3
	KCNC2	NM_001414196.1		c.1781A>G	p.Asp594Gly	missense splice_region	Exon 4 of 5	NP_001401125.1	Q96PR1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC2	ENST00000548513.5	TSL:1	c.1781A>G	p.Asp594Gly	missense splice_region	Exon 4 of 5	ENSP00000449941.1	Q96PR1-3
	KCNC2	ENST00000549446.6	TSL:1 MANE Select	c.*731A>G		3_prime_UTR	Exon 5 of 5	ENSP00000449253.2	Q96PR1-1
	KCNC2	ENST00000550433.5	TSL:1	c.1781-1168A>G		intron	N/A	ENSP00000448301.1	Q96PR1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249862 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459024 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725832

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110162

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	19
DANN	Benign	0.95
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.90	D
PhyloP100		5.3
PROVEAN	Benign	0.67	N
REVEL	Uncertain	0.49
Sift	Benign	0.28	T
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.84
ClinPred		0.30	T
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0068
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.14		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: rs201339164; hg19: chr12-75436154;