chr19-50320275-C-T
Variant names:
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_004977.3(KCNC3):c.2245G>A(p.Ala749Thr) 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: 𝑓 0.000047 ( 0 hom., cov: 16)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
KCNC3
NM_004977.3 missense
NM_004977.3 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 2.92
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]
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ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.25157288).
BS1
Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000556 (51/916716) while in subpopulation NFE AF = 0.0000662 (48/724782). AF 95% confidence interval is 0.0000513. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 13. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNC3 | NM_004977.3 | c.2245G>A | p.Ala749Thr | missense_variant | Exon 4 of 5 | ENST00000477616.2 | NP_004968.2 | |
KCNC3 | NM_001372305.1 | c.2017G>A | p.Ala673Thr | missense_variant | Exon 4 of 5 | NP_001359234.1 | ||
KCNC3 | NR_110912.2 | n.260+318G>A | intron_variant | Intron 2 of 3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNC3 | ENST00000477616.2 | c.2245G>A | p.Ala749Thr | missense_variant | Exon 4 of 5 | 1 | NM_004977.3 | ENSP00000434241.1 | ||
KCNC3 | ENST00000670667.1 | c.2170+318G>A | intron_variant | Intron 3 of 3 | ENSP00000499301.1 | |||||
KCNC3 | ENST00000376959.6 | c.2170+318G>A | intron_variant | Intron 3 of 4 | 5 | ENSP00000366158.2 | ||||
KCNC3 | ENST00000474951.1 | c.118+318G>A | intron_variant | Intron 2 of 3 | 2 | ENSP00000432438.1 |
Frequencies
GnomAD3 genomes AF: 0.0000467 AC: 6AN: 128458Hom.: 0 Cov.: 16 show subpopulations
GnomAD3 genomes
AF:
AC:
6
AN:
128458
Hom.:
Cov.:
16
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GnomAD2 exomes AF: 0.0000528 AC: 3AN: 56842 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
56842
AF XY:
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GnomAD4 exome AF: 0.0000556 AC: 51AN: 916716Hom.: 0 Cov.: 13 AF XY: 0.0000562 AC XY: 25AN XY: 444648 show subpopulations
GnomAD4 exome
AF:
AC:
51
AN:
916716
Hom.:
Cov.:
13
AF XY:
AC XY:
25
AN XY:
444648
Gnomad4 AFR exome
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0
AN:
21636
Gnomad4 AMR exome
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AC:
0
AN:
15058
Gnomad4 ASJ exome
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0
AN:
14720
Gnomad4 EAS exome
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0
AN:
28858
Gnomad4 SAS exome
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1
AN:
37340
Gnomad4 FIN exome
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AC:
0
AN:
31988
Gnomad4 NFE exome
AF:
AC:
48
AN:
724782
Gnomad4 Remaining exome
AF:
AC:
2
AN:
39240
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
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Age
GnomAD4 genome AF: 0.0000467 AC: 6AN: 128458Hom.: 0 Cov.: 16 AF XY: 0.0000328 AC XY: 2AN XY: 60942 show subpopulations
GnomAD4 genome
AF:
AC:
6
AN:
128458
Hom.:
Cov.:
16
AF XY:
AC XY:
2
AN XY:
60942
Gnomad4 AFR
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AC:
0
AN:
0
Gnomad4 AMR
AF:
AC:
0.0000872448
AN:
0.0000872448
Gnomad4 ASJ
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0
AN:
0
Gnomad4 EAS
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AC:
0
AN:
0
Gnomad4 SAS
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0
AN:
0
Gnomad4 FIN
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AC:
0
AN:
0
Gnomad4 NFE
AF:
AC:
0.0000802105
AN:
0.0000802105
Gnomad4 OTH
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AC:
0
AN:
0
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Sep 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Spinocerebellar ataxia type 13 Uncertain:1
Nov 18, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of helix (P = 0.0376);
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Mutation Taster
=96/4
polymorphism
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at