1-110601794-A-ATGTG

Variant names:

• chr1-110601794-A-ATGTG
• rs35728918
• NM_004974.4:c.*1485_*1488dupCACA

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.*1485_*1488dupCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 0)
  • Exomes 𝑓: 0.0029 (1 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.335
• 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-A-ATGTG is Benign according to our data. Variant chr1-110601794-A-ATGTG is described in ClinVar as [Likely_benign]. Clinvar id is 1190501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0079 (1074/135946) while in subpopulation AFR AF = 0.0221 (758/34362). AF 95% confidence interval is 0.0208. There are 8 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1074 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1485_*1488dupCACA		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.*1485_*1488dupCACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1070 AN: 135898 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00364

Gnomad ASJ AF: 0.00120

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00711

Gnomad FIN AF: 0.000836

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.0107

GnomAD4 exome AF: 0.00290 AC: 2035 AN: 702496 Hom.: 1 Cov.: 6 AF XY: 0.00294 AC XY: 988 AN XY: 335700

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

African (AFR) AF: 0.0143 AC: 208 AN: 14532

American (AMR) AF: 0.00281 AC: 15 AN: 5336

Ashkenazi Jewish (ASJ) AF: 0.00162 AC: 15 AN: 9250

East Asian (EAS) AF: 0.00272 AC: 39 AN: 14356

South Asian (SAS) AF: 0.00697 AC: 88 AN: 12626

European-Finnish (FIN) AF: 0.00185 AC: 19 AN: 10266

Middle Eastern (MID) AF: 0.00634 AC: 12 AN: 1894

European-Non Finnish (NFE) AF: 0.00253 AC: 1533 AN: 606858

Other (OTH) AF: 0.00387 AC: 106 AN: 27378

⚠️ 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: 0.00790 AC: 1074 AN: 135946 Hom.: 8 Cov.: 0 AF XY: 0.00804 AC XY: 526 AN XY: 65448

African (AFR) AF: 0.0221 AC: 758 AN: 34362

American (AMR) AF: 0.00364 AC: 49 AN: 13458

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 4 AN: 3330

East Asian (EAS) AF: 0.00403 AC: 18 AN: 4462

South Asian (SAS) AF: 0.00786 AC: 32 AN: 4070

European-Finnish (FIN) AF: 0.000836 AC: 7 AN: 8376

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.00285 AC: 185 AN: 64848

Other (OTH) AF: 0.0106 AC: 20 AN: 1890

Alfa AF: 0.00 Hom.: 69

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 24, 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		0.34
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: rs35728918; hg19: chr1-111144416;