1-110623233-C-G

Variant names:

• chr1-110623233-C-G
• rs3908929
• ENST00000369770.7:c.-496+8162G>C

Variant summary

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

The ENST00000369770.7(KCNA2):​c.-496+8162G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 152,152 control chromosomes in the GnomAD database, including 51,229 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 0.82 (51229 hom., cov: 32)
• Consequence: KCNA2 ENST00000369770.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 1 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_001204269.2	c.-496+8162G>C		intron_variant	Intron 1 of 4		NP_001191198.1
KCNA2	XM_011541398.3	c.-496+8136G>C		intron_variant	Intron 1 of 2		XP_011539700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000369770.7	c.-496+8162G>C		intron_variant	Intron 1 of 4	1		ENSP00000358785.3

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124646 AN: 152034 Hom.: 51189 Cov.: 32

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.860

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.835

Gnomad OTH AF: 0.809

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

GnomAD4 genome AF: 0.820 AC: 124741 AN: 152152 Hom.: 51229 Cov.: 32 AF XY: 0.818 AC XY: 60873 AN XY: 74392

African (AFR) AF: 0.801 AC: 33222 AN: 41482

American (AMR) AF: 0.815 AC: 12465 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.860 AC: 2984 AN: 3470

East Asian (EAS) AF: 0.713 AC: 3692 AN: 5180

South Asian (SAS) AF: 0.773 AC: 3729 AN: 4824

European-Finnish (FIN) AF: 0.879 AC: 9323 AN: 10606

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.835 AC: 56735 AN: 67984

Other (OTH) AF: 0.809 AC: 1708 AN: 2112

Alfa AF: 0.831 Hom.: 6514

Bravo AF: 0.816

Asia WGS AF: 0.763 AC: 2651 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.48
DANN	Benign	0.50
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3908929; hg19: chr1-111165855;