1-110601828-G-GTGTGTGTATA

Variant names:

• chr1-110601828-G-GTGTGTGTATA
• rs763912060
• NM_004974.4:c.*1454_*1455insTATACACACA

Variant summary

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

The NM_004974.4(KCNA2):​c.*1454_*1455insTATACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000696 in 143,642 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 0.0000070 (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_*1455insTATACACACA		3_prime_UTR	Exon 3 of 3	NP_004965.1	P16389-1
	KCNA2	NM_001204269.2		c.1035+201_1035+202insTATACACACA		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_*1455insTATACACACA		3_prime_UTR	Exon 3 of 3	ENSP00000314520.4	P16389-1
	KCNA2	ENST00000369770.7	TSL:1	c.1035+201_1035+202insTATACACACA		intron	N/A	ENSP00000358785.3	P16389-2
	KCNA2	ENST00000633222.1	TSL:5	c.*1454_*1455insTATACACACA		3_prime_UTR	Exon 3 of 3	ENSP00000487785.1	P16389-1

Frequencies

GnomAD3 genomes AF: 0.00000697 AC: 1 AN: 143566 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000221

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 Data not reliable, filtered out with message: AS_VQSR AF: 9.08e-7 AC: 1 AN: 1100854 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 528140

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: 0.0000436 AC: 1 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: 0.00 AC: 0 AN: 921040

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

GnomAD4 genome AF: 0.00000696 AC: 1 AN: 143642 Hom.: 0 Cov.: 28 AF XY: 0.0000144 AC XY: 1 AN XY: 69538

African (AFR) AF: 0.00 AC: 0 AN: 38382

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

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

East Asian (EAS) AF: 0.000222 AC: 1 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

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;