1-110601794-ATGTG-A

Variant names:

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

Variant summary

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

The NM_004974.4(KCNA2):​c.*1485_*1488delCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0589 in 830,402 control chromosomes in the GnomAD database, including 391 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (194 hom., cov: 0)
  • Exomes 𝑓: 0.060 (197 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-ATGTG-A is Benign according to our data. Variant chr1-110601794-ATGTG-A is described in ClinVar as [Benign]. Clinvar id is 1274548.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7060 AN: 135822 Hom.: 195 Cov.: 0

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.0651

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00916

Gnomad SAS AF: 0.0444

Gnomad FIN AF: 0.0520

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.0416

GnomAD4 exome AF: 0.0602 AC: 41819 AN: 694534 Hom.: 197 AF XY: 0.0602 AC XY: 19989 AN XY: 331932

African (AFR) AF: 0.0714 AC: 1021 AN: 14294

American (AMR) AF: 0.0558 AC: 295 AN: 5286

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 294 AN: 9136

East Asian (EAS) AF: 0.00845 AC: 121 AN: 14324

South Asian (SAS) AF: 0.0615 AC: 770 AN: 12514

European-Finnish (FIN) AF: 0.0666 AC: 674 AN: 10126

Middle Eastern (MID) AF: 0.0313 AC: 58 AN: 1854

European-Non Finnish (NFE) AF: 0.0618 AC: 37096 AN: 599934

Other (OTH) AF: 0.0551 AC: 1490 AN: 27066

GnomAD4 genome AF: 0.0519 AC: 7056 AN: 135868 Hom.: 194 Cov.: 0 AF XY: 0.0503 AC XY: 3292 AN XY: 65406

African (AFR) AF: 0.0599 AC: 2056 AN: 34342

American (AMR) AF: 0.0325 AC: 437 AN: 13454

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 77 AN: 3328

East Asian (EAS) AF: 0.00918 AC: 41 AN: 4464

South Asian (SAS) AF: 0.0440 AC: 179 AN: 4066

European-Finnish (FIN) AF: 0.0520 AC: 435 AN: 8362

Middle Eastern (MID) AF: 0.0255 AC: 7 AN: 274

European-Non Finnish (NFE) AF: 0.0569 AC: 3689 AN: 64812

Other (OTH) AF: 0.0413 AC: 78 AN: 1890

Alfa AF: 0.0310 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		0.39
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;