chr1-110601792-A-ATGTG

Variant names:

• chr1-110601792-A-ATGTG
• rs1379102271
• NM_004974.4:c.*1490_*1491insCACA

Variant summary

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

The NM_004974.4(KCNA2):​c.*1490_*1491insCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 139,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: 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.*1490_*1491insCACA		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_*1491insCACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.000623 AC: 87 AN: 139566 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.000354

Gnomad ASJ AF: 0.000586

Gnomad EAS AF: 0.00129

Gnomad SAS AF: 0.000468

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000440

Gnomad OTH AF: 0.000513

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000186 AC: 180 AN: 970068 Hom.: 0 Cov.: 18 AF XY: 0.000189 AC XY: 87 AN XY: 459386

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

African (AFR) AF: 0.000202 AC: 4 AN: 19784

American (AMR) AF: 0.000725 AC: 5 AN: 6900

Ashkenazi Jewish (ASJ) AF: 0.000317 AC: 4 AN: 12606

East Asian (EAS) AF: 0.00 AC: 0 AN: 18530

South Asian (SAS) AF: 0.000109 AC: 2 AN: 18312

European-Finnish (FIN) AF: 0.000140 AC: 2 AN: 14268

Middle Eastern (MID) AF: 0.000392 AC: 1 AN: 2552

European-Non Finnish (NFE) AF: 0.000182 AC: 153 AN: 839062

Other (OTH) AF: 0.000237 AC: 9 AN: 38054

⚠️ 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: 0.000623 AC: 87 AN: 139664 Hom.: 0 Cov.: 29 AF XY: 0.000532 AC XY: 36 AN XY: 67662

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

African (AFR) AF: 0.00116 AC: 40 AN: 34620

American (AMR) AF: 0.000354 AC: 5 AN: 14122

Ashkenazi Jewish (ASJ) AF: 0.000586 AC: 2 AN: 3414

East Asian (EAS) AF: 0.00129 AC: 6 AN: 4638

South Asian (SAS) AF: 0.000469 AC: 2 AN: 4266

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9500

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

European-Non Finnish (NFE) AF: 0.000440 AC: 29 AN: 65970

Other (OTH) AF: 0.000508 AC: 1 AN: 1968

⚠️ 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: 0.00 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

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;