1-110601792-ATATG-A

Variant names:

• chr1-110601792-ATATG-A
• rs1411300455
• NM_004974.4:c.*1487_*1490delCATA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004974.4(KCNA2):​c.*1487_*1490delCATA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,108,042 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.89
• 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 -10 ACMG points.

• BP6: Variant 1-110601792-ATATG-A is Benign according to our data. Variant chr1-110601792-ATATG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1204366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00525 (733/139606) while in subpopulation AFR AF = 0.0171 (590/34568). AF 95% confidence interval is 0.0159. There are 2 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 733 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1487_*1490delCATA		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.*1487_*1490delCATA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 728 AN: 139510 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00205

Gnomad EAS AF: 0.000215

Gnomad SAS AF: 0.000936

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00205

GnomAD4 exome AF: 0.00173 AC: 1674 AN: 968436 Hom.: 0 AF XY: 0.00180 AC XY: 825 AN XY: 458630

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

African (AFR) AF: 0.0148 AC: 290 AN: 19636

American (AMR) AF: 0.00262 AC: 18 AN: 6872

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 36 AN: 12534

East Asian (EAS) AF: 0.00173 AC: 32 AN: 18452

South Asian (SAS) AF: 0.000655 AC: 12 AN: 18308

European-Finnish (FIN) AF: 0.00183 AC: 26 AN: 14220

Middle Eastern (MID) AF: 0.00157 AC: 4 AN: 2540

European-Non Finnish (NFE) AF: 0.00141 AC: 1184 AN: 837928

Other (OTH) AF: 0.00190 AC: 72 AN: 37946

⚠️ 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: 0.00525 AC: 733 AN: 139606 Hom.: 2 Cov.: 0 AF XY: 0.00504 AC XY: 341 AN XY: 67636

African (AFR) AF: 0.0171 AC: 590 AN: 34568

American (AMR) AF: 0.00170 AC: 24 AN: 14118

Ashkenazi Jewish (ASJ) AF: 0.00205 AC: 7 AN: 3414

East Asian (EAS) AF: 0.000216 AC: 1 AN: 4638

South Asian (SAS) AF: 0.000938 AC: 4 AN: 4266

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00155 AC: 102 AN: 65968

Other (OTH) AF: 0.00203 AC: 4 AN: 1968

Alfa AF: 0.00443 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

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: rs1411300455; hg19: chr1-111144414;