rs763912060

Variant names:

• chr1-110601828-G-GTGTA
• rs763912060
• NM_004974.4:c.*1454_*1455insTACA

Your query was ambiguous. Multiple possible variants found:

• chr1-110601828-G-GTGTA
• chr1-110601828-G-GTGTATA
• chr1-110601828-G-GTGTGTA
• chr1-110601828-G-GTGTGTATA
• chr1-110601828-G-GTGTGTC
• chr1-110601828-G-GTGTGTGTA
• chr1-110601828-G-GTGTGTGTATA
• chr1-110601828-G-GTGTGTGTGTA
• chr1-110601828-G-GTGTGTGTGTATA
• chr1-110601828-G-GTGTGTGTGTGTA
• chr1-110601828-G-GTGTGTGTGTGTGTA
• chr1-110601828-G-GTGTGTGTGTGTGTGTA
• chr1-110601828-G-GTGTGTGTGTGTGTGTGTA
• chr1-110601828-G-GTGTGTGTGTGTGTGTGTGTA
• chr1-110601828-G-GTGTGTGTGTGTGTGTGTGTGTA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004974.4(KCNA2):​c.*1454_*1455insTACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,237,206 control chromosomes in the GnomAD database, including 14 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0044 (12 hom., cov: 28)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00437 (628/143554) while in subpopulation EAS AF = 0.0451 (202/4476). AF 95% confidence interval is 0.04. There are 12 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 628 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1454_*1455insTACA		3_prime_UTR_variant	Exon 3 of 3	ENST00000316361.10	NP_004965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10	c.*1454_*1455insTACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 621 AN: 143478 Hom.: 11 Cov.: 28

Gnomad AFR AF: 0.00272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00380

Gnomad EAS AF: 0.0447

Gnomad SAS AF: 0.00273

Gnomad FIN AF: 0.00338

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00404

GnomAD4 exome AF: 0.00133 AC: 1458 AN: 1093652 Hom.: 2 Cov.: 27 AF XY: 0.00138 AC XY: 726 AN XY: 524810

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000886 AC: 20 AN: 22580

American (AMR) AF: 0.00934 AC: 100 AN: 10702

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 19 AN: 16024

East Asian (EAS) AF: 0.0281 AC: 629 AN: 22408

South Asian (SAS) AF: 0.00114 AC: 41 AN: 36076

European-Finnish (FIN) AF: 0.00329 AC: 74 AN: 22514

Middle Eastern (MID) AF: 0.000978 AC: 3 AN: 3068

European-Non Finnish (NFE) AF: 0.000543 AC: 497 AN: 915428

Other (OTH) AF: 0.00167 AC: 75 AN: 44852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00437 AC: 628 AN: 143554 Hom.: 12 Cov.: 28 AF XY: 0.00447 AC XY: 311 AN XY: 69500

African (AFR) AF: 0.00276 AC: 106 AN: 38368

American (AMR) AF: 0.00912 AC: 127 AN: 13926

Ashkenazi Jewish (ASJ) AF: 0.00380 AC: 13 AN: 3420

East Asian (EAS) AF: 0.0451 AC: 202 AN: 4476

South Asian (SAS) AF: 0.00296 AC: 13 AN: 4390

European-Finnish (FIN) AF: 0.00338 AC: 32 AN: 9468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00193 AC: 128 AN: 66324

Other (OTH) AF: 0.00351 AC: 7 AN: 1996

Alfa AF: 0.00154 Hom.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.060

Splicing

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

Other links and lift over

dbSNP: rs763912060; hg19: chr1-111144450;