NM_004974.4:c.*1454_*1455insTACACACACACACACACA

Variant names:

• chr1-110601828-G-GTGTGTGTGTGTGTGTGTA
• rs763912060
• NM_004974.4:c.*1454_*1455insTACACACACACACACACA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004974.4(KCNA2):​c.*1454_*1455insTACACACACACACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,244,378 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1454_*1455insTACACACACACACACACA		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.*1454_*1455insTACACACACACACACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0000209 AC: 3 AN: 143562 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000318 AC: 35 AN: 1100740 Hom.: 0 Cov.: 27 AF XY: 0.0000379 AC XY: 20 AN XY: 528088

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

African (AFR) AF: 0.0000441 AC: 1 AN: 22698

American (AMR) AF: 0.000185 AC: 2 AN: 10814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16080

East Asian (EAS) AF: 0.000785 AC: 18 AN: 22934

South Asian (SAS) AF: 0.000247 AC: 9 AN: 36396

European-Finnish (FIN) AF: 0.0000443 AC: 1 AN: 22552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3092

European-Non Finnish (NFE) AF: 0.00000434 AC: 4 AN: 920970

Other (OTH) AF: 0.00 AC: 0 AN: 45204

⚠️ 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: 0.0000209 AC: 3 AN: 143638 Hom.: 0 Cov.: 28 AF XY: 0.0000288 AC XY: 2 AN XY: 69534

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

African (AFR) AF: 0.0000782 AC: 3 AN: 38378

American (AMR) AF: 0.00 AC: 0 AN: 13944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4502

South Asian (SAS) AF: 0.00 AC: 0 AN: 4394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66340

Other (OTH) AF: 0.00 AC: 0 AN: 1998

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000005), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.060

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763912060; hg19: chr1-111144450;