NM_004974.4:c.1185G>C

Variant names:

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

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

KCNA2 links:

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
KCNA2	NM_004974.4 link	c.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
KCNA2	ENST00000316361.10 link	c.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.:

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.:

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:

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

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

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.:

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0523

AC:

3557

AN:

67984

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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

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.:

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

(source)

DANN

Benign

0.70

PhyloP100

-0.18

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over