chr12-4912182-G-C

Position:

chr12-4912182-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000217.3(KCNA1):c.804G>C(p.Thr268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,612,204 control chromosomes in the GnomAD database, including 215,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 19642 hom., cov: 27)

Exomes 𝑓: 0.52 ( 196221 hom. )

Consequence

KCNA1
NM_000217.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.640

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 links:

(HGNC:):

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=-0.59).

BP6

Variant 12-4912182-G-C is Benign according to our data. Variant chr12-4912182-G-C is described in ClinVar as [Benign]. Clinvar id is 21130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4912182-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.64 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA1	NM_000217.3 linkuse as main transcript	c.804G>C	p.Thr268=	synonymous_variant	2/2	ENST00000382545.5	NP_000208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5 linkuse as main transcript	c.804G>C	p.Thr268=	synonymous_variant	2/2	4	NM_000217.3	ENSP00000371985	P1
	ENST00000640877.1 linkuse as main transcript	n.606+1710G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.508

AC:

76460

AN:

150484

Hom.:

19629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.521

Gnomad AMR

AF:

0.581

Gnomad ASJ

AF:

0.580

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.481

Gnomad FIN

AF:

0.487

Gnomad MID

AF:

0.656

Gnomad NFE

AF:

0.511

Gnomad OTH

AF:

0.528

GnomAD3 exomes

AF:

0.532

AC:

133633

AN:

251292

Hom.:

36097

AF XY:

0.528

AC XY:

71684

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.455

Gnomad AMR exome

AF:

0.632

Gnomad ASJ exome

AF:

0.590

Gnomad EAS exome

AF:

0.656

Gnomad SAS exome

AF:

0.473

Gnomad FIN exome

AF:

0.487

Gnomad NFE exome

AF:

0.511

Gnomad OTH exome

AF:

0.530

GnomAD4 exome

AF:

0.516

AC:

753596

AN:

1461602

Hom.:

196221

Cov.:

AF XY:

0.514

AC XY:

373941

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.461

Gnomad4 AMR exome

AF:

0.625

Gnomad4 ASJ exome

AF:

0.590

Gnomad4 EAS exome

AF:

0.642

Gnomad4 SAS exome

AF:

0.476

Gnomad4 FIN exome

AF:

0.487

Gnomad4 NFE exome

AF:

0.510

Gnomad4 OTH exome

AF:

0.523

GnomAD4 genome

AF:

0.508

AC:

76505

AN:

150602

Hom.:

19642

Cov.:

AF XY:

0.510

AC XY:

37388

AN XY:

73348

show subpopulations

Gnomad4 AFR

AF:

0.460

Gnomad4 AMR

AF:

0.581

Gnomad4 ASJ

AF:

0.580

Gnomad4 EAS

AF:

0.645

Gnomad4 SAS

AF:

0.480

Gnomad4 FIN

AF:

0.487

Gnomad4 NFE

AF:

0.510

Gnomad4 OTH

AF:

0.532

Alfa

AF:

0.480

Hom.:

5126

Bravo

AF:

0.519

Asia WGS

AF:

0.576

AC:

1998

AN:

3478

EpiCase

AF:

0.524

EpiControl

AF:

0.526

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 77% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 72. Only high quality variants are reported. -

Episodic ataxia type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

Hereditary episodic ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.4

DANN

Benign

0.73

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

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