chr1-110527682-A-G

Variant names:

• chr1-110527682-A-G
• rs7553815
• ENST00000640680.1:n.2731+5068T>C

Variant summary

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

The ENST00000640680.1(KCNA2):​n.2731+5068T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,268 control chromosomes in the GnomAD database, including 1,321 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 0.13 (1321 hom., cov: 33)
• Consequence: KCNA2 ENST00000640680.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498
• Publications: 0 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

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 (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000640680.1	n.2731+5068T>C		intron_variant	Intron 6 of 8	5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19149 AN: 152150 Hom.: 1321 Cov.: 33

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.126 AC: 19160 AN: 152268 Hom.: 1321 Cov.: 33 AF XY: 0.126 AC XY: 9351 AN XY: 74448

African (AFR) AF: 0.0808 AC: 3359 AN: 41554

American (AMR) AF: 0.145 AC: 2216 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3468

East Asian (EAS) AF: 0.0461 AC: 239 AN: 5188

South Asian (SAS) AF: 0.209 AC: 1005 AN: 4820

European-Finnish (FIN) AF: 0.132 AC: 1405 AN: 10604

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9948 AN: 68016

Other (OTH) AF: 0.138 AC: 292 AN: 2116

Alfa AF: 0.141 Hom.: 2511

Bravo AF: 0.123

Asia WGS AF: 0.134 AC: 466 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	0.16
DANN	Benign	0.54
PhyloP100		-0.50

Splicing

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

Other links and lift over

dbSNP: rs7553815; hg19: chr1-111070304;