1-110601794-ATGTGTGTGTGTGTGTGTGTGTG-ATGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

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

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

• Frequency:
  • Genomes: 𝑓 0.13 (1419 hom., cov: 0)
  • Exomes 𝑓: 0.14 (222 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: 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-ATG is Benign according to our data. Variant chr1-110601794-A-ATG is described in ClinVar as [Benign]. Clinvar id is 1251062.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.133 AC: 17989 AN: 135618 Hom.: 1417 Cov.: 0

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0544

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.135 AC: 91742 AN: 677428 Hom.: 222 Cov.: 6 AF XY: 0.136 AC XY: 43917 AN XY: 323568

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

African (AFR) AF: 0.0230 AC: 334 AN: 14526

American (AMR) AF: 0.0589 AC: 311 AN: 5276

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 766 AN: 9030

East Asian (EAS) AF: 0.126 AC: 1779 AN: 14096

South Asian (SAS) AF: 0.119 AC: 1461 AN: 12234

European-Finnish (FIN) AF: 0.101 AC: 1020 AN: 10052

Middle Eastern (MID) AF: 0.0771 AC: 144 AN: 1868

European-Non Finnish (NFE) AF: 0.142 AC: 82728 AN: 583790

Other (OTH) AF: 0.120 AC: 3199 AN: 26556

⚠️ 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: 0.133 AC: 17986 AN: 135670 Hom.: 1419 Cov.: 0 AF XY: 0.128 AC XY: 8363 AN XY: 65298

African (AFR) AF: 0.0402 AC: 1379 AN: 34344

American (AMR) AF: 0.0855 AC: 1149 AN: 13434

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 334 AN: 3322

East Asian (EAS) AF: 0.189 AC: 842 AN: 4460

South Asian (SAS) AF: 0.179 AC: 728 AN: 4058

European-Finnish (FIN) AF: 0.122 AC: 1022 AN: 8346

Middle Eastern (MID) AF: 0.0547 AC: 15 AN: 274

European-Non Finnish (NFE) AF: 0.188 AC: 12137 AN: 64672

Other (OTH) AF: 0.113 AC: 213 AN: 1888

Alfa AF: 0.0686 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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;