19-50320289-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004977.3(KCNC3):​c.2231T>C​(p.Leu744Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 16)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNC3
NM_004977.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.462

Publications

0 publications found
Variant links:
Genes affected
KCNC3 (HGNC:6235): (potassium voltage-gated channel subfamily C member 3) 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. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]
KCNC3 Gene-Disease associations (from GenCC):
  • spinocerebellar ataxia type 13
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21747905).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNC3NM_004977.3 linkc.2231T>C p.Leu744Ser missense_variant Exon 4 of 5 ENST00000477616.2 NP_004968.2 Q14003
KCNC3NM_001372305.1 linkc.2003T>C p.Leu668Ser missense_variant Exon 4 of 5 NP_001359234.1
KCNC3NR_110912.2 linkn.260+304T>C intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNC3ENST00000477616.2 linkc.2231T>C p.Leu744Ser missense_variant Exon 4 of 5 1 NM_004977.3 ENSP00000434241.1 Q14003
KCNC3ENST00000670667.1 linkc.2170+304T>C intron_variant Intron 3 of 3 ENSP00000499301.1 A0A590UJ62
KCNC3ENST00000376959.6 linkc.2170+304T>C intron_variant Intron 3 of 4 5 ENSP00000366158.2 E7ETH1
KCNC3ENST00000474951.1 linkc.118+304T>C intron_variant Intron 2 of 3 2 ENSP00000432438.1 E9PQY4

Frequencies

GnomAD3 genomes
Cov.:
16
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
793994
Hom.:
0
Cov.:
13
AF XY:
0.00
AC XY:
0
AN XY:
383866
African (AFR)
AF:
0.00
AC:
0
AN:
18702
American (AMR)
AF:
0.00
AC:
0
AN:
12752
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
11286
East Asian (EAS)
AF:
0.00
AC:
0
AN:
19328
South Asian (SAS)
AF:
0.00
AC:
0
AN:
39014
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
21796
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2560
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
636286
Other (OTH)
AF:
0.00
AC:
0
AN:
32270
GnomAD4 genome
Cov.:
16

ClinVar

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

Submissions by phenotype

Spinocerebellar ataxia type 13 Uncertain:1
Aug 15, 2024
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ACMG classification criteria: PM2 supporting, BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.37
T
M_CAP
Pathogenic
0.64
D
MetaRNN
Benign
0.22
T
MetaSVM
Uncertain
-0.0070
T
MutationAssessor
Benign
0.0
N
PhyloP100
0.46
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.69
N
REVEL
Uncertain
0.38
Sift
Uncertain
0.012
D
Sift4G
Uncertain
0.057
T
Polyphen
0.81
P
Vest4
0.32
MutPred
0.13
Gain of glycosylation at L744 (P = 0.0049);
MVP
0.64
ClinPred
0.26
T
GERP RS
1.2
Varity_R
0.095
gMVP
0.30
Mutation Taster
=93/7
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

hg19: chr19-50823546; API