1-110601777-AATATATAT-AATATAT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004974.4(KCNA2):​c.*1504_*1505delAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 979,066 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 22)
  • Exomes 𝑓: 0.0055 (1 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 381 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 380 AN: 140398 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00619

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.000336

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000726

Gnomad OTH AF: 0.00157

GnomAD4 exome AF: 0.00547 AC: 4587 AN: 838582 Hom.: 1 AF XY: 0.00556 AC XY: 2197 AN XY: 395348

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

African (AFR) AF: 0.0106 AC: 180 AN: 17050

American (AMR) AF: 0.00828 AC: 50 AN: 6040

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 153 AN: 9830

East Asian (EAS) AF: 0.0149 AC: 266 AN: 17888

South Asian (SAS) AF: 0.00447 AC: 68 AN: 15220

European-Finnish (FIN) AF: 0.0189 AC: 207 AN: 10940

Middle Eastern (MID) AF: 0.0149 AC: 32 AN: 2144

European-Non Finnish (NFE) AF: 0.00460 AC: 3349 AN: 727400

Other (OTH) AF: 0.00879 AC: 282 AN: 32070

⚠️ 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: 0.00271 AC: 381 AN: 140484 Hom.: 2 Cov.: 22 AF XY: 0.00264 AC XY: 179 AN XY: 67834

African (AFR) AF: 0.00734 AC: 276 AN: 37596

American (AMR) AF: 0.00115 AC: 16 AN: 13928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.00621 AC: 29 AN: 4672

South Asian (SAS) AF: 0.00168 AC: 7 AN: 4164

European-Finnish (FIN) AF: 0.000336 AC: 3 AN: 8928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000726 AC: 47 AN: 64752

Other (OTH) AF: 0.00155 AC: 3 AN: 1930

Alfa AF: 0.00 Hom.: 99

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs149560146; hg19: chr1-111144399;