chr1-110601828-G-GTA

Variant names:

• chr1-110601828-G-GTA
• rs1553181014
• NM_004974.4:c.*1453_*1454dupTA

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.*1453_*1454dupTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,225,606 control chromosomes in the GnomAD database, including 171 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (10 hom., cov: 28)
  • Exomes 𝑓: 0.0073 (161 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-110601828-G-GTA is Benign according to our data. Variant chr1-110601828-G-GTA is described in ClinVar as [Likely_benign]. Clinvar id is 1212933.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00628 (902/143552) while in subpopulation AFR AF = 0.0196 (753/38352). AF 95% confidence interval is 0.0185. There are 10 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 902 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1453_*1454dupTA		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.*1453_*1454dupTA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00627 AC: 899 AN: 143474 Hom.: 10 Cov.: 28

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00467

Gnomad ASJ AF: 0.00468

Gnomad EAS AF: 0.00400

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000634

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000347

Gnomad OTH AF: 0.00554

GnomAD4 exome AF: 0.00734 AC: 7939 AN: 1082054 Hom.: 161 Cov.: 27 AF XY: 0.00721 AC XY: 3744 AN XY: 519248

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

African (AFR) AF: 0.0260 AC: 572 AN: 22028

American (AMR) AF: 0.0246 AC: 262 AN: 10672

Ashkenazi Jewish (ASJ) AF: 0.00673 AC: 107 AN: 15908

East Asian (EAS) AF: 0.0211 AC: 473 AN: 22428

South Asian (SAS) AF: 0.0194 AC: 686 AN: 35418

European-Finnish (FIN) AF: 0.00556 AC: 125 AN: 22498

Middle Eastern (MID) AF: 0.00526 AC: 16 AN: 3040

European-Non Finnish (NFE) AF: 0.00581 AC: 5259 AN: 905792

Other (OTH) AF: 0.00992 AC: 439 AN: 44270

⚠️ 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: 0.00628 AC: 902 AN: 143552 Hom.: 10 Cov.: 28 AF XY: 0.00619 AC XY: 430 AN XY: 69486

African (AFR) AF: 0.0196 AC: 753 AN: 38352

American (AMR) AF: 0.00459 AC: 64 AN: 13932

Ashkenazi Jewish (ASJ) AF: 0.00468 AC: 16 AN: 3422

East Asian (EAS) AF: 0.00401 AC: 18 AN: 4486

South Asian (SAS) AF: 0.00228 AC: 10 AN: 4388

European-Finnish (FIN) AF: 0.000634 AC: 6 AN: 9470

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000347 AC: 23 AN: 66318

Other (OTH) AF: 0.00551 AC: 11 AN: 1998

Alfa AF: 0.00 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

- -

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: rs1553181014; hg19: chr1-111144450;