NM_139137.4:c.1769G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_139137.4(KCNC2):​c.1769G>C​(p.Gly590Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,612,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

KCNC2
NM_139137.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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=0.08265498).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000289 (44/152056) while in subpopulation AFR AF= 0.00104 (43/41430). AF 95% confidence interval is 0.000791. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNC2NM_139137.4 linkc.1769G>C p.Gly590Ala missense_variant Exon 4 of 5 ENST00000549446.6 NP_631875.1 Q96PR1-1A0A024RBA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNC2ENST00000549446.6 linkc.1769G>C p.Gly590Ala missense_variant Exon 4 of 5 1 NM_139137.4 ENSP00000449253.2 Q96PR1-1

Frequencies

GnomAD3 genomes
AF:
0.000289
AC:
44
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
250708
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135528
show subpopulations
Gnomad AFR exome
AF:
0.000865
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1460516
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726584
show subpopulations
Gnomad4 AFR exome
AF:
0.000750
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000289
AC:
44
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.000283
AC XY:
21
AN XY:
74252
show subpopulations
Gnomad4 AFR
AF:
0.00104
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000356
Hom.:
0
Bravo
AF:
0.000325
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Sep 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1769G>C (p.G590A) alteration is located in exon 4 (coding exon 3) of the KCNC2 gene. This alteration results from a G to C substitution at nucleotide position 1769, causing the glycine (G) at amino acid position 590 to be replaced by an alanine (A). 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
Benign
0.079
BayesDel_addAF
Benign
-0.0073
T
BayesDel_noAF
Uncertain
0.13
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.22
.;.;T;.;.
Eigen
Benign
0.016
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.89
D;.;T;D;D
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.083
T;T;T;T;T
MetaSVM
Uncertain
0.51
D
MutationAssessor
Benign
1.2
L;L;L;L;L
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.79
N;N;N;N;N
REVEL
Uncertain
0.45
Sift
Benign
0.11
T;T;T;T;T
Sift4G
Benign
0.13
T;T;T;T;T
Polyphen
0.016
B;B;B;B;.
Vest4
0.48
MVP
0.88
MPC
1.0
ClinPred
0.078
T
GERP RS
5.5
Varity_R
0.16
gMVP
0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs151248231; hg19: chr12-75441944; API