1-110601828-G-GTGTGTATA

Variant names:

• chr1-110601828-G-GTGTGTATA
• rs763912060
• NM_004974.4:c.*1454_*1455insTATACACA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004974.4(KCNA2):​c.*1454_*1455insTATACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 143,640 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 28)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• 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: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA2	NM_004974.4	MANE Select	c.*1454_*1455insTATACACA		3_prime_UTR	Exon 3 of 3	NP_004965.1	P16389-1
	KCNA2	NM_001204269.2		c.1035+201_1035+202insTATACACA		intron	N/A	NP_001191198.1	P16389-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA2	ENST00000316361.10	TSL:2 MANE Select	c.*1454_*1455insTATACACA		3_prime_UTR	Exon 3 of 3	ENSP00000314520.4	P16389-1
	KCNA2	ENST00000369770.7	TSL:1	c.1035+201_1035+202insTATACACA		intron	N/A	ENSP00000358785.3	P16389-2
	KCNA2	ENST00000633222.1	TSL:5	c.*1454_*1455insTATACACA		3_prime_UTR	Exon 3 of 3	ENSP00000487785.1	P16389-1

Frequencies

GnomAD3 genomes AF: 0.0000279 AC: 4 AN: 143564 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000718

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.08e-7 AC: 1 AN: 1100854 Hom.: 0 Cov.: 27 AF XY: 0.00000189 AC XY: 1 AN XY: 528140

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

African (AFR) AF: 0.00 AC: 0 AN: 22712

American (AMR) AF: 0.00 AC: 0 AN: 10814

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 22952

South Asian (SAS) AF: 0.00 AC: 0 AN: 36402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22552

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

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 921040

Other (OTH) AF: 0.00 AC: 0 AN: 45210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000278 AC: 4 AN: 143640 Hom.: 0 Cov.: 28 AF XY: 0.0000288 AC XY: 2 AN XY: 69536

African (AFR) AF: 0.0000521 AC: 2 AN: 38380

American (AMR) AF: 0.0000717 AC: 1 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: 0.000228 AC: 1 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

Alfa AF: 0.00 Hom.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;