12-4910895-A-AG

Variant names:

• chr12-4910895-A-AG
• rs34346629
• NM_000217.3:c.-478dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000217.3(KCNA1):​c.-478dupG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00917 in 183,470 control chromosomes in the GnomAD database, including 43 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (42 hom., cov: 31)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: KCNA1 NM_000217.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.847
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 12-4910895-A-AG is Benign according to our data. Variant chr12-4910895-A-AG is described in ClinVar as [Likely_benign]. Clinvar id is 309133.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1661/150572) while in subpopulation AFR AF = 0.0384 (1569/40860). AF 95% confidence interval is 0.0368. There are 42 homozygotes in GnomAd4. There are 757 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA1	NM_000217.3	c.-478dupG		5_prime_UTR_variant	Exon 2 of 2	ENST00000382545.5	NP_000208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5	c.-478dupG		5_prime_UTR_variant	Exon 2 of 2	4	NM_000217.3	ENSP00000371985.3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1654 AN: 150456 Hom.: 41 Cov.: 31

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00436

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00725

GnomAD4 exome AF: 0.000638 AC: 21 AN: 32898 Hom.: 1 Cov.: 0 AF XY: 0.000660 AC XY: 11 AN XY: 16668

African (AFR) AF: 0.0321 AC: 10 AN: 312

American (AMR) AF: 0.00187 AC: 5 AN: 2674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 584

East Asian (EAS) AF: 0.00 AC: 0 AN: 1044

South Asian (SAS) AF: 0.000284 AC: 1 AN: 3526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 116

European-Non Finnish (NFE) AF: 0.0000483 AC: 1 AN: 20706

Other (OTH) AF: 0.00207 AC: 4 AN: 1936

GnomAD4 genome AF: 0.0110 AC: 1661 AN: 150572 Hom.: 42 Cov.: 31 AF XY: 0.0103 AC XY: 757 AN XY: 73506

African (AFR) AF: 0.0384 AC: 1569 AN: 40860

American (AMR) AF: 0.00435 AC: 66 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67606

Other (OTH) AF: 0.00718 AC: 15 AN: 2090

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.0122

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary episodic ataxia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myokymia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=257/43	polymorphism

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: rs34346629; hg19: chr12-5020061;