rs17025978

Variant names:

• chr1-110526989-G-A
• rs17025978
• ENST00000640680.1:n.2732-4691C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000640680.1(KCNA2):​n.2732-4691C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 152,254 control chromosomes in the GnomAD database, including 743 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.091 (743 hom., cov: 33)
• Consequence: KCNA2 ENST00000640680.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.172
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 32

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ENSG00000301555 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124904292	XR_007066353.1	n.*162G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000640680.1	n.2732-4691C>T		intron_variant	Intron 6 of 8	5
ENSG00000301555	ENST00000779684.1	n.*164G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0906 AC: 13783 AN: 152138 Hom.: 739 Cov.: 33

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0998

Gnomad OTH AF: 0.101

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0906 AC: 13800 AN: 152254 Hom.: 743 Cov.: 33 AF XY: 0.0909 AC XY: 6763 AN XY: 74420

African (AFR) AF: 0.0529 AC: 2197 AN: 41560

American (AMR) AF: 0.129 AC: 1979 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.153 AC: 790 AN: 5180

South Asian (SAS) AF: 0.150 AC: 721 AN: 4814

European-Finnish (FIN) AF: 0.0693 AC: 735 AN: 10604

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0998 AC: 6788 AN: 68016

Other (OTH) AF: 0.101 AC: 214 AN: 2116

Alfa AF: 0.0998 Hom.: 2525

Bravo AF: 0.0938

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.5
DANN	Benign	0.37
PhyloP100		-0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17025978; hg19: chr1-111069611;