12-4912182-G-C

Variant names:

• chr12-4912182-G-C
• rs2227910
• NM_000217.3:c.804G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000217.3(KCNA1):​c.804G>C​(p.Thr268Thr) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T268T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.51 (19642 hom., cov: 27)
  • Exomes 𝑓: 0.52 (196221 hom.)
• Consequence: KCNA1 NM_000217.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.640
• Publications: 23 publications found

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

ENSG00000256654 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 21130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000217.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	NM_000217.3	MANE Select	c.804G>C	p.Thr268Thr	synonymous	Exon 2 of 2	NP_000208.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.804G>C	p.Thr268Thr	synonymous	Exon 2 of 2	ENSP00000371985.3
	KCNA1	ENST00000639306.1	TSL:5	n.642G>C		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1
	ENSG00000256654	ENST00000541095.1	TSL:3	n.105+1710G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.508 AC: 76460 AN: 150484 Hom.: 19629 Cov.: 27

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

GnomAD2 exomes AF: 0.532 AC: 133633 AN: 251292 AF XY: 0.528

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 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.: 59 AF XY: 0.514 AC XY: 373941 AN XY: 727132

African (AFR) AF: 0.461 AC: 15444 AN: 33478

American (AMR) AF: 0.625 AC: 27958 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 15413 AN: 26136

East Asian (EAS) AF: 0.642 AC: 25472 AN: 39700

South Asian (SAS) AF: 0.476 AC: 41067 AN: 86258

European-Finnish (FIN) AF: 0.487 AC: 25971 AN: 53298

Middle Eastern (MID) AF: 0.592 AC: 3417 AN: 5768

European-Non Finnish (NFE) AF: 0.510 AC: 567260 AN: 1111850

Other (OTH) AF: 0.523 AC: 31594 AN: 60392

GnomAD4 genome AF: 0.508 AC: 76505 AN: 150602 Hom.: 19642 Cov.: 27 AF XY: 0.510 AC XY: 37388 AN XY: 73348

African (AFR) AF: 0.460 AC: 18844 AN: 40986

American (AMR) AF: 0.581 AC: 8818 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2005 AN: 3458

East Asian (EAS) AF: 0.645 AC: 3240 AN: 5024

South Asian (SAS) AF: 0.480 AC: 2249 AN: 4686

European-Finnish (FIN) AF: 0.487 AC: 5004 AN: 10272

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.510 AC: 34570 AN: 67720

Other (OTH) AF: 0.532 AC: 1110 AN: 2088

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

Submissions by phenotype

not specified Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Episodic ataxia type 1 Benign:3

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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.

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary episodic ataxia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.4
DANN	Benign	0.73
PhyloP100		-0.64
PromoterAI		0.033	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2227910; hg19: chr12-5021348; COSMIC: COSV66836881; COSMIC: COSV66836881;