1-110601794-ATG-A

Variant names:

• chr1-110601794-ATG-A
• rs35728918
• NM_004974.4:c.*1487_*1488delCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004974.4(KCNA2):​c.*1487_*1488delCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.063 in 803,640 control chromosomes in the GnomAD database, including 508 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (461 hom., cov: 0)
  • Exomes 𝑓: 0.062 (47 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.391
• 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 1-110601794-ATG-A is Benign according to our data. Variant chr1-110601794-ATG-A is described in ClinVar as [Benign]. Clinvar id is 1251556.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1487_*1488delCA		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_*1488delCA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0678 AC: 9194 AN: 135554 Hom.: 461 Cov.: 0

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.0316

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0850

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.0620 AC: 41387 AN: 668038 Hom.: 47 AF XY: 0.0628 AC XY: 20046 AN XY: 318978

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

African (AFR) AF: 0.161 AC: 2227 AN: 13830

American (AMR) AF: 0.0759 AC: 387 AN: 5102

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 1178 AN: 8500

East Asian (EAS) AF: 0.0649 AC: 910 AN: 14012

South Asian (SAS) AF: 0.0661 AC: 799 AN: 12080

European-Finnish (FIN) AF: 0.0964 AC: 923 AN: 9572

Middle Eastern (MID) AF: 0.108 AC: 187 AN: 1734

European-Non Finnish (NFE) AF: 0.0569 AC: 32823 AN: 577342

Other (OTH) AF: 0.0755 AC: 1953 AN: 25866

⚠️ 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: 0.0679 AC: 9204 AN: 135602 Hom.: 461 Cov.: 0 AF XY: 0.0682 AC XY: 4453 AN XY: 65254

African (AFR) AF: 0.156 AC: 5320 AN: 34200

American (AMR) AF: 0.0431 AC: 580 AN: 13444

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 265 AN: 3328

East Asian (EAS) AF: 0.0574 AC: 256 AN: 4458

South Asian (SAS) AF: 0.0312 AC: 127 AN: 4066

European-Finnish (FIN) AF: 0.0370 AC: 309 AN: 8344

Middle Eastern (MID) AF: 0.0839 AC: 23 AN: 274

European-Non Finnish (NFE) AF: 0.0334 AC: 2163 AN: 64728

Other (OTH) AF: 0.0589 AC: 111 AN: 1884

Alfa AF: 0.0197 Hom.: 69

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: 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		0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs35728918; hg19: chr1-111144416;