NM_004974.4:c.1185G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004974.4(KCNA2):​c.1185G>C​(p.Ala395Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,613,908 control chromosomes in the GnomAD database, including 2,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A395A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.044 ( 192 hom., cov: 32)
Exomes 𝑓: 0.051 ( 2340 hom. )

Consequence

KCNA2
NM_004974.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.177

Publications

7 publications found
Variant links:
Genes affected
KCNA2 (HGNC:6220): (potassium voltage-gated channel subfamily A member 2) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1. [provided by RefSeq, Jul 2008]
KCNA2 Gene-Disease associations (from GenCC):
  • developmental and epileptic encephalopathy, 32
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • genetic developmental and epileptic encephalopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • undetermined early-onset epileptic encephalopathy
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
Variant 1-110603598-C-G is Benign according to our data. Variant chr1-110603598-C-G is described in ClinVar as [Benign]. Clinvar id is 447615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.177 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0832 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNA2NM_004974.4 linkc.1185G>C p.Ala395Ala synonymous_variant Exon 3 of 3 ENST00000316361.10 NP_004965.1 P16389-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNA2ENST00000316361.10 linkc.1185G>C p.Ala395Ala synonymous_variant Exon 3 of 3 2 NM_004974.4 ENSP00000314520.4 P16389-1

Frequencies

GnomAD3 genomes
AF:
0.0438
AC:
6663
AN:
152034
Hom.:
191
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0152
Gnomad AMI
AF:
0.0603
Gnomad AMR
AF:
0.0364
Gnomad ASJ
AF:
0.108
Gnomad EAS
AF:
0.000577
Gnomad SAS
AF:
0.0897
Gnomad FIN
AF:
0.0912
Gnomad MID
AF:
0.0411
Gnomad NFE
AF:
0.0523
Gnomad OTH
AF:
0.0382
GnomAD2 exomes
AF:
0.0529
AC:
13302
AN:
251392
AF XY:
0.0561
show subpopulations
Gnomad AFR exome
AF:
0.0177
Gnomad AMR exome
AF:
0.0222
Gnomad ASJ exome
AF:
0.105
Gnomad EAS exome
AF:
0.000381
Gnomad FIN exome
AF:
0.0910
Gnomad NFE exome
AF:
0.0534
Gnomad OTH exome
AF:
0.0611
GnomAD4 exome
AF:
0.0514
AC:
75116
AN:
1461756
Hom.:
2340
Cov.:
34
AF XY:
0.0529
AC XY:
38504
AN XY:
727192
show subpopulations
African (AFR)
AF:
0.0145
AC:
487
AN:
33480
American (AMR)
AF:
0.0234
AC:
1046
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.108
AC:
2830
AN:
26136
East Asian (EAS)
AF:
0.000453
AC:
18
AN:
39700
South Asian (SAS)
AF:
0.0901
AC:
7769
AN:
86258
European-Finnish (FIN)
AF:
0.0900
AC:
4798
AN:
53316
Middle Eastern (MID)
AF:
0.0787
AC:
454
AN:
5768
European-Non Finnish (NFE)
AF:
0.0491
AC:
54545
AN:
1111978
Other (OTH)
AF:
0.0525
AC:
3169
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.472
Heterozygous variant carriers
0
4420
8840
13259
17679
22099
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2014
4028
6042
8056
10070
<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:
0.0439
AC:
6672
AN:
152152
Hom.:
192
Cov.:
32
AF XY:
0.0461
AC XY:
3427
AN XY:
74378
show subpopulations
African (AFR)
AF:
0.0152
AC:
629
AN:
41518
American (AMR)
AF:
0.0363
AC:
555
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.108
AC:
374
AN:
3470
East Asian (EAS)
AF:
0.000579
AC:
3
AN:
5184
South Asian (SAS)
AF:
0.0902
AC:
434
AN:
4810
European-Finnish (FIN)
AF:
0.0912
AC:
965
AN:
10580
Middle Eastern (MID)
AF:
0.0408
AC:
12
AN:
294
European-Non Finnish (NFE)
AF:
0.0523
AC:
3557
AN:
67984
Other (OTH)
AF:
0.0416
AC:
88
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
314
628
942
1256
1570
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
84
168
252
336
420
<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:
0.0454
Hom.:
76
Bravo
AF:
0.0371
Asia WGS
AF:
0.0510
AC:
175
AN:
3478
EpiCase
AF:
0.0582
EpiControl
AF:
0.0537

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jul 15, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Jun 22, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 32 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Feb 24, 2016
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
CADD
Benign
0.91
DANN
Benign
0.70
PhyloP100
-0.18
Mutation Taster
=97/3
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs78349687; hg19: chr1-111146220; COSMIC: COSV60369493; API