chr12-4912503-C-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS1

The NM_000217.3(KCNA1):​c.1125C>T​(p.Tyr375Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,864 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 29)
Exomes 𝑓: 0.00083 ( 0 hom. )

Consequence

KCNA1
NM_000217.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.965

Publications

1 publications found
Variant links:
Genes affected
KCNA1 (HGNC:6218): (potassium voltage-gated channel subfamily A member 1) This gene encodes a voltage-gated delayed potassium channel that is phylogenetically related to the Drosophila Shaker channel. The encoded protein has six putative transmembrane segments (S1-S6), and the loop between S5 and S6 forms the pore and contains the conserved selectivity filter motif (GYGD). The functional channel is a homotetramer. The N-terminus of the channel is associated with beta subunits that can modify the inactivation properties of the channel as well as affect expression levels. The C-terminus of the channel is complexed to a PDZ domain protein that is responsible for channel targeting. Mutations in this gene have been associated with myokymia with periodic ataxia (AEMK). [provided by RefSeq, Jul 2008]
KCNA1 Gene-Disease associations (from GenCC):
  • episodic ataxia type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • episodic kinesigenic dyskinesia 1
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • isolated autosomal dominant hypomagnesemia, Glaudemans type
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • genetic developmental and epileptic encephalopathy
    Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 12-4912503-C-T is Benign according to our data. Variant chr12-4912503-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 309146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.965 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000395 (60/152048) while in subpopulation NFE AF = 0.000765 (52/67996). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNA1NM_000217.3 linkc.1125C>T p.Tyr375Tyr synonymous_variant Exon 2 of 2 ENST00000382545.5 NP_000208.2 Q09470

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNA1ENST00000382545.5 linkc.1125C>T p.Tyr375Tyr synonymous_variant Exon 2 of 2 4 NM_000217.3 ENSP00000371985.3 Q09470

Frequencies

GnomAD3 genomes
AF:
0.000395
AC:
60
AN:
151930
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000765
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000354
AC:
89
AN:
251368
AF XY:
0.000353
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000686
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000828
AC:
1211
AN:
1461816
Hom.:
0
Cov.:
42
AF XY:
0.000756
AC XY:
550
AN XY:
727212
show subpopulations
African (AFR)
AF:
0.000149
AC:
5
AN:
33480
American (AMR)
AF:
0.000224
AC:
10
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00104
AC:
1158
AN:
1111962
Other (OTH)
AF:
0.000629
AC:
38
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
80
160
241
321
401
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
52
104
156
208
260
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000395
AC:
60
AN:
152048
Hom.:
0
Cov.:
29
AF XY:
0.000310
AC XY:
23
AN XY:
74308
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41456
American (AMR)
AF:
0.0000654
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5150
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4798
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10584
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000765
AC:
52
AN:
67996
Other (OTH)
AF:
0.00
AC:
0
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000523
Hom.:
0
Bravo
AF:
0.000385
EpiCase
AF:
0.000872
EpiControl
AF:
0.000830

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Episodic ataxia type 1 Benign:4
Mar 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 10, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:3
May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

KCNA1: BP4, BP7 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Hereditary episodic ataxia Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Jun 09, 2017
Athena Diagnostics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

KCNA1-related disorder Benign:1
Jun 07, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
9.3
DANN
Benign
0.59
PhyloP100
0.96
PromoterAI
0.0066
Neutral
Mutation Taster
=97/3
polymorphism

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

Other links and lift over

dbSNP: rs144351014; hg19: chr12-5021669; COSMIC: COSV66836624; API