1-110601777-AATATATAT-AATAT

Variant names:

• chr1-110601777-AATAT-A
• rs149560146
• NM_004974.4:c.*1502_*1505delATAT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004974.4(KCNA2):​c.*1502_*1505delATAT variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000474 in 985,854 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1502_*1505delATAT		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.*1502_*1505delATAT		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.000242 AC: 34 AN: 140424 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000359

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000511 AC: 432 AN: 845344 Hom.: 0 AF XY: 0.000507 AC XY: 202 AN XY: 398638

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

African (AFR) AF: 0.00495 AC: 85 AN: 17182

American (AMR) AF: 0.000815 AC: 5 AN: 6138

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 13 AN: 10128

East Asian (EAS) AF: 0.000947 AC: 17 AN: 17960

South Asian (SAS) AF: 0.000526 AC: 8 AN: 15196

European-Finnish (FIN) AF: 0.000443 AC: 5 AN: 11284

Middle Eastern (MID) AF: 0.00137 AC: 3 AN: 2182

European-Non Finnish (NFE) AF: 0.000360 AC: 264 AN: 732822

Other (OTH) AF: 0.000986 AC: 32 AN: 32452

⚠️ 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: 0.000249 AC: 35 AN: 140510 Hom.: 0 Cov.: 22 AF XY: 0.000236 AC XY: 16 AN XY: 67842

African (AFR) AF: 0.000745 AC: 28 AN: 37604

American (AMR) AF: 0.000359 AC: 5 AN: 13932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.000214 AC: 1 AN: 4672

South Asian (SAS) AF: 0.00 AC: 0 AN: 4166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64758

Other (OTH) AF: 0.00 AC: 0 AN: 1932

Alfa AF: 0.00 Hom.: 99

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

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: rs149560146; hg19: chr1-111144399;