1-110601792-ATATGTG-A

Variant names:

• chr1-110601792-ATATGTG-A
• rs1400312833
• NM_004974.4:c.*1485_*1490delCACATA

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_*1490delCACATA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,107,570 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 0)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.89
• 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 1-110601792-ATATGTG-A is Benign according to our data. Variant chr1-110601792-ATATGTG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1196513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1411/139586) while in subpopulation AFR AF = 0.0381 (1317/34546). AF 95% confidence interval is 0.0364. There are 17 homozygotes in GnomAd4. There are 638 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1411 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1485_*1490delCACATA		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_*1490delCACATA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1407 AN: 139488 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00411

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000215

Gnomad SAS AF: 0.000936

Gnomad FIN AF: 0.000316

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000167

Gnomad OTH AF: 0.00924

GnomAD4 exome AF: 0.000996 AC: 964 AN: 967984 Hom.: 0 AF XY: 0.000892 AC XY: 409 AN XY: 458378

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

African (AFR) AF: 0.0313 AC: 610 AN: 19466

American (AMR) AF: 0.00218 AC: 15 AN: 6874

Ashkenazi Jewish (ASJ) AF: 0.000398 AC: 5 AN: 12576

East Asian (EAS) AF: 0.000108 AC: 2 AN: 18518

South Asian (SAS) AF: 0.000273 AC: 5 AN: 18284

European-Finnish (FIN) AF: 0.00155 AC: 22 AN: 14180

Middle Eastern (MID) AF: 0.00157 AC: 4 AN: 2542

European-Non Finnish (NFE) AF: 0.000258 AC: 216 AN: 837590

Other (OTH) AF: 0.00224 AC: 85 AN: 37954

⚠️ 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: 0.0101 AC: 1411 AN: 139586 Hom.: 17 Cov.: 0 AF XY: 0.00943 AC XY: 638 AN XY: 67626

African (AFR) AF: 0.0381 AC: 1317 AN: 34546

American (AMR) AF: 0.00411 AC: 58 AN: 14120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.000216 AC: 1 AN: 4638

South Asian (SAS) AF: 0.000703 AC: 3 AN: 4266

European-Finnish (FIN) AF: 0.000316 AC: 3 AN: 9500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000167 AC: 11 AN: 65970

Other (OTH) AF: 0.00916 AC: 18 AN: 1966

Alfa AF: 0.00902 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 26, 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		1.9
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: rs1400312833; hg19: chr1-111144414;