NM_000217.3:c.-428C>T

Variant names:

• chr12-4910951-C-T
• rs7307690
• NM_000217.3:c.-428C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000217.3(KCNA1):​c.-428C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 208,474 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: KCNA1 NM_000217.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.437
• 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: Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• episodic kinesigenic dyskinesia 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P
• isolated autosomal dominant hypomagnesemia, Glaudemans type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256654 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-4910951-C-T is Benign according to our data. Variant chr12-4910951-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309135.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00285 (432/151610) while in subpopulation AFR AF = 0.0101 (418/41334). AF 95% confidence interval is 0.00931. There are 3 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	NM_000217.3	MANE Select	c.-428C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	NP_000208.2	Q09470
	KCNA1	NM_000217.3	MANE Select	c.-428C>T		5_prime_UTR	Exon 2 of 2	NP_000208.2	Q09470

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.-428C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000371985.3	Q09470
	KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.-428C>T		5_prime_UTR	Exon 2 of 2	ENSP00000371985.3	Q09470
	ENSG00000256654	ENST00000541095.1	TSL:3	n.105+479C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 430 AN: 151492 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

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: 0.0000147

Gnomad OTH AF: 0.00241

GnomAD4 exome AF: 0.000404 AC: 23 AN: 56864 Hom.: 1 Cov.: 0 AF XY: 0.000310 AC XY: 9 AN XY: 29012

African (AFR) AF: 0.0168 AC: 15 AN: 892

American (AMR) AF: 0.00180 AC: 6 AN: 3338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1240

East Asian (EAS) AF: 0.00 AC: 0 AN: 2092

South Asian (SAS) AF: 0.00 AC: 0 AN: 6794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 35654

Other (OTH) AF: 0.000613 AC: 2 AN: 3262

GnomAD4 genome AF: 0.00285 AC: 432 AN: 151610 Hom.: 3 Cov.: 31 AF XY: 0.00275 AC XY: 204 AN XY: 74070

African (AFR) AF: 0.0101 AC: 418 AN: 41334

American (AMR) AF: 0.000525 AC: 8 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67864

Other (OTH) AF: 0.00239 AC: 5 AN: 2096

Alfa AF: 0.00184 Hom.: 1

Bravo AF: 0.00348

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Episodic ataxia type 1 (1)
-	-	1	Hereditary episodic ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		-0.44

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: rs7307690; hg19: chr12-5020117;