1-110601828-G-GTGTGTGTGTA

Variant names:

• chr1-110601828-G-GTGTGTGTGTA
• rs763912060
• NM_004974.4:c.*1454_*1455insTACACACACA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004974.4(KCNA2):​c.*1454_*1455insTACACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,239,200 control chromosomes in the GnomAD database, including 28 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (27 hom., cov: 28)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-110601828-G-GTGTGTGTGTA is Benign according to our data. Variant chr1-110601828-G-GTGTGTGTGTA is described in ClinVar as [Likely_benign]. Clinvar id is 1213655.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2528 AN: 142862 Hom.: 27 Cov.: 28

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.0596

Gnomad SAS AF: 0.0297

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.00884

Gnomad OTH AF: 0.0218

GnomAD4 exome AF: 0.00183 AC: 2004 AN: 1096264 Hom.: 1 Cov.: 27 AF XY: 0.00199 AC XY: 1049 AN XY: 525922

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

African (AFR) AF: 0.00633 AC: 142 AN: 22426

American (AMR) AF: 0.00804 AC: 86 AN: 10702

Ashkenazi Jewish (ASJ) AF: 0.000187 AC: 3 AN: 16072

East Asian (EAS) AF: 0.0278 AC: 622 AN: 22380

South Asian (SAS) AF: 0.00255 AC: 92 AN: 36110

European-Finnish (FIN) AF: 0.00943 AC: 211 AN: 22378

Middle Eastern (MID) AF: 0.00162 AC: 5 AN: 3082

European-Non Finnish (NFE) AF: 0.000742 AC: 681 AN: 918156

Other (OTH) AF: 0.00360 AC: 162 AN: 44958

⚠️ 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: 0.0177 AC: 2529 AN: 142936 Hom.: 27 Cov.: 28 AF XY: 0.0186 AC XY: 1288 AN XY: 69210

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

African (AFR) AF: 0.0275 AC: 1049 AN: 38158

American (AMR) AF: 0.0197 AC: 273 AN: 13866

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3422

East Asian (EAS) AF: 0.0596 AC: 263 AN: 4414

South Asian (SAS) AF: 0.0293 AC: 128 AN: 4366

European-Finnish (FIN) AF: 0.0197 AC: 185 AN: 9408

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.00885 AC: 585 AN: 66134

Other (OTH) AF: 0.0217 AC: 43 AN: 1982

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00414 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 21, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.060
Mutation Taster		=100/0	polymorphism

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;