1-110603598-C-G

Position:

chr1-110603598-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 links:

KCNA2 (HGNC:):

KCNA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
KCNA2	NM_004974.4 linkuse as main transcript	c.1185G>C	p.Ala395Ala	synonymous_variant	3/3	ENST00000316361.10	NP_004965.1	P16389-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10 linkuse as main transcript	c.1185G>C	p.Ala395Ala	synonymous_variant	3/3	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

GnomAD3 exomes

AF:

0.0529

AC:

13302

AN:

251392

Hom.:

533

AF XY:

0.0561

AC XY:

7617

AN XY:

135872

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 SAS exome

AF:

0.0902

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

Gnomad4 AFR exome

AF:

0.0145

Gnomad4 AMR exome

AF:

0.0234

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.000453

Gnomad4 SAS exome

AF:

0.0901

Gnomad4 FIN exome

AF:

0.0900

Gnomad4 NFE exome

AF:

0.0491

Gnomad4 OTH exome

AF:

0.0525

GnomAD4 genome

AF:

0.0439

AC:

6672

AN:

152152

Hom.:

192

Cov.:

AF XY:

0.0461

AC XY:

3427

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.0363

Gnomad4 ASJ

AF:

0.108

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0902

Gnomad4 FIN

AF:

0.0912

Gnomad4 NFE

AF:

0.0523

Gnomad4 OTH

AF:

0.0416

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 22, 2017

- -

Developmental and epileptic encephalopathy, 32

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2016

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over