1-110601777-AATATAT-A

Variant names:

• chr1-110601777-AATATAT-A
• rs149560146
• NM_004974.4:c.*1500_*1505delATATAT

Variant summary

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

The NM_004974.4(KCNA2):​c.*1500_*1505delATATAT variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00107 in 140,494 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 0.0011 (0 hom., cov: 22)
  • Exomes 𝑓: 0.012 (375 hom.)
  • Failed GnomAD Quality Control
• 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 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1500_*1505delATATAT		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.*1500_*1505delATATAT		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 150 AN: 140408 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.000595

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.00144

Gnomad FIN AF: 0.000672

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000201

Gnomad OTH AF: 0.000522

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0124 AC: 10508 AN: 844664 Hom.: 375 AF XY: 0.0120 AC XY: 4779 AN XY: 398280

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

African (AFR) AF: 0.0142 AC: 245 AN: 17206

American (AMR) AF: 0.00944 AC: 58 AN: 6142

Ashkenazi Jewish (ASJ) AF: 0.00503 AC: 51 AN: 10140

East Asian (EAS) AF: 0.0136 AC: 245 AN: 17992

South Asian (SAS) AF: 0.0348 AC: 528 AN: 15156

European-Finnish (FIN) AF: 0.00115 AC: 13 AN: 11304

Middle Eastern (MID) AF: 0.00779 AC: 17 AN: 2182

European-Non Finnish (NFE) AF: 0.0121 AC: 8876 AN: 732130

Other (OTH) AF: 0.0147 AC: 475 AN: 32412

⚠️ 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: 0.00107 AC: 150 AN: 140494 Hom.: 0 Cov.: 22 AF XY: 0.00125 AC XY: 85 AN XY: 67830

African (AFR) AF: 0.00285 AC: 107 AN: 37604

American (AMR) AF: 0.000718 AC: 10 AN: 13932

Ashkenazi Jewish (ASJ) AF: 0.000595 AC: 2 AN: 3364

East Asian (EAS) AF: 0.00107 AC: 5 AN: 4666

South Asian (SAS) AF: 0.00144 AC: 6 AN: 4166

European-Finnish (FIN) AF: 0.000672 AC: 6 AN: 8932

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

European-Non Finnish (NFE) AF: 0.000201 AC: 13 AN: 64752

Other (OTH) AF: 0.000518 AC: 1 AN: 1932

Alfa AF: 0.000669 Hom.: 99

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Splicing

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

Other links and lift over

dbSNP: rs149560146; hg19: chr1-111144399;