1-110601777-A-AAT

Variant names:

• chr1-110601777-A-AAT
• rs149560146
• NM_004974.4:c.*1504_*1505dupAT

Variant summary

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

The NM_004974.4(KCNA2):​c.*1504_*1505dupAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 139,726 control chromosomes in the GnomAD database, including 2,479 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2479 hom., cov: 22)
  • Exomes 𝑓: 0.13 (632 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.61
• 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 1-110601777-A-AAT is Benign according to our data. Variant chr1-110601777-A-AAT is described in ClinVar as [Benign]. Clinvar id is 1270237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1504_*1505dupAT		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.*1504_*1505dupAT		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.188 AC: 26243 AN: 139644 Hom.: 2479 Cov.: 22

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.215

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.132 AC: 103734 AN: 782948 Hom.: 632 Cov.: 15 AF XY: 0.134 AC XY: 49393 AN XY: 369264

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

African (AFR) AF: 0.0941 AC: 1545 AN: 16410

American (AMR) AF: 0.121 AC: 720 AN: 5934

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 1245 AN: 9532

East Asian (EAS) AF: 0.0753 AC: 1329 AN: 17648

South Asian (SAS) AF: 0.0977 AC: 1419 AN: 14522

European-Finnish (FIN) AF: 0.0965 AC: 1054 AN: 10926

Middle Eastern (MID) AF: 0.118 AC: 238 AN: 2020

European-Non Finnish (NFE) AF: 0.136 AC: 92145 AN: 675558

Other (OTH) AF: 0.133 AC: 4039 AN: 30398

⚠️ 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: 0.188 AC: 26241 AN: 139726 Hom.: 2479 Cov.: 22 AF XY: 0.183 AC XY: 12332 AN XY: 67466

African (AFR) AF: 0.141 AC: 5285 AN: 37414

American (AMR) AF: 0.210 AC: 2912 AN: 13862

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 689 AN: 3348

East Asian (EAS) AF: 0.135 AC: 627 AN: 4656

South Asian (SAS) AF: 0.163 AC: 676 AN: 4140

European-Finnish (FIN) AF: 0.136 AC: 1201 AN: 8854

Middle Eastern (MID) AF: 0.191 AC: 54 AN: 282

European-Non Finnish (NFE) AF: 0.221 AC: 14263 AN: 64396

Other (OTH) AF: 0.215 AC: 411 AN: 1916

Alfa AF: 0.0749 Hom.: 99

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		1.6
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: rs149560146; hg19: chr1-111144399; COSMIC: COSV60369937; COSMIC: COSV60369937;