chr1-110601777-A-AATAT

Variant names:

• chr1-110601777-A-AATAT
• rs149560146
• NM_004974.4:c.*1502_*1505dupATAT

Variant summary

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

The NM_004974.4(KCNA2):​c.*1502_*1505dupATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 140,502 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00094 (1 hom., cov: 22)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• 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 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1502_*1505dupATAT		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.*1502_*1505dupATAT		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 132 AN: 140416 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000863

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.00128

Gnomad SAS AF: 0.000718

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00157

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00157 AC: 1329 AN: 846982 Hom.: 0 Cov.: 15 AF XY: 0.00151 AC XY: 603 AN XY: 399364

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

African (AFR) AF: 0.00139 AC: 24 AN: 17222

American (AMR) AF: 0.00163 AC: 10 AN: 6150

Ashkenazi Jewish (ASJ) AF: 0.00178 AC: 18 AN: 10124

East Asian (EAS) AF: 0.000885 AC: 16 AN: 18078

South Asian (SAS) AF: 0.00241 AC: 37 AN: 15368

European-Finnish (FIN) AF: 0.00133 AC: 15 AN: 11290

Middle Eastern (MID) AF: 0.000459 AC: 1 AN: 2180

European-Non Finnish (NFE) AF: 0.00157 AC: 1153 AN: 734016

Other (OTH) AF: 0.00169 AC: 55 AN: 32554

⚠️ 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: 0.000939 AC: 132 AN: 140502 Hom.: 1 Cov.: 22 AF XY: 0.000929 AC XY: 63 AN XY: 67836

African (AFR) AF: 0.00104 AC: 39 AN: 37602

American (AMR) AF: 0.000861 AC: 12 AN: 13932

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 4 AN: 3368

East Asian (EAS) AF: 0.00128 AC: 6 AN: 4672

South Asian (SAS) AF: 0.000720 AC: 3 AN: 4166

European-Finnish (FIN) AF: 0.000112 AC: 1 AN: 8930

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

European-Non Finnish (NFE) AF: 0.000988 AC: 64 AN: 64756

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

Alfa AF: 0.00134 Hom.: 99

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs149560146; hg19: chr1-111144399;