NM_004974.4:c.*1490_*1491insCA

Variant names:

• chr1-110601792-A-ATG
• rs1379102271
• NM_004974.4:c.*1490_*1491insCA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004974.4(KCNA2):​c.*1490_*1491insCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 139,420 control chromosomes in the GnomAD database, including 41 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (41 hom., cov: 29)
  • Exomes 𝑓: 0.012 (3 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-110601792-A-ATG is Benign according to our data. Variant chr1-110601792-A-ATG is described in ClinVar as [Likely_benign]. Clinvar id is 1201388.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1490_*1491insCA		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.*1490_*1491insCA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3003 AN: 139322 Hom.: 41 Cov.: 29

Gnomad AFR AF: 0.00679

Gnomad AMI AF: 0.0375

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0397

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0149

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0121 AC: 11608 AN: 959578 Hom.: 3 Cov.: 18 AF XY: 0.0124 AC XY: 5626 AN XY: 454412

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

African (AFR) AF: 0.00299 AC: 59 AN: 19746

American (AMR) AF: 0.00929 AC: 64 AN: 6888

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 153 AN: 12552

East Asian (EAS) AF: 0.00146 AC: 27 AN: 18526

South Asian (SAS) AF: 0.00897 AC: 163 AN: 18174

European-Finnish (FIN) AF: 0.0325 AC: 462 AN: 14206

Middle Eastern (MID) AF: 0.0231 AC: 58 AN: 2510

European-Non Finnish (NFE) AF: 0.0122 AC: 10148 AN: 829238

Other (OTH) AF: 0.0126 AC: 474 AN: 37738

⚠️ 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: 0.0216 AC: 3006 AN: 139420 Hom.: 41 Cov.: 29 AF XY: 0.0222 AC XY: 1498 AN XY: 67548

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

African (AFR) AF: 0.00688 AC: 238 AN: 34598

American (AMR) AF: 0.0206 AC: 291 AN: 14102

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 59 AN: 3410

East Asian (EAS) AF: 0.00194 AC: 9 AN: 4636

South Asian (SAS) AF: 0.0178 AC: 76 AN: 4260

European-Finnish (FIN) AF: 0.0435 AC: 412 AN: 9466

Middle Eastern (MID) AF: 0.0423 AC: 12 AN: 284

European-Non Finnish (NFE) AF: 0.0281 AC: 1847 AN: 65822

Other (OTH) AF: 0.0148 AC: 29 AN: 1962

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00962 Hom.: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 22, 2020

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: rs1379102271; hg19: chr1-111144414;