1-110601828-G-GTGTGTGTGTGTA

Variant names:

• chr1-110601828-G-GTGTGTGTGTGTA
• rs763912060
• NM_004974.4:c.*1454_*1455insTACACACACACA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004974.4(KCNA2):​c.*1454_*1455insTACACACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,242,092 control chromosomes in the GnomAD database, including 8 homozygotes. 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 (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 28)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-110601828-G-GTGTGTGTGTGTA is Benign according to our data. Variant chr1-110601828-G-GTGTGTGTGTGTA is described in ClinVar as [Likely_benign]. Clinvar id is 1211180.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1134 AN: 143110 Hom.: 8 Cov.: 28

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.00524

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00658

GnomAD4 exome AF: 0.000880 AC: 967 AN: 1098902 Hom.: 0 Cov.: 27 AF XY: 0.000920 AC XY: 485 AN XY: 527246

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

African (AFR) AF: 0.00284 AC: 64 AN: 22558

American (AMR) AF: 0.00483 AC: 52 AN: 10762

Ashkenazi Jewish (ASJ) AF: 0.000249 AC: 4 AN: 16074

East Asian (EAS) AF: 0.0239 AC: 538 AN: 22554

South Asian (SAS) AF: 0.00121 AC: 44 AN: 36308

European-Finnish (FIN) AF: 0.00397 AC: 89 AN: 22440

Middle Eastern (MID) AF: 0.000647 AC: 2 AN: 3090

European-Non Finnish (NFE) AF: 0.000137 AC: 126 AN: 920008

Other (OTH) AF: 0.00106 AC: 48 AN: 45108

⚠️ 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: 0.00792 AC: 1134 AN: 143190 Hom.: 8 Cov.: 28 AF XY: 0.00825 AC XY: 572 AN XY: 69298

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

African (AFR) AF: 0.0194 AC: 740 AN: 38090

American (AMR) AF: 0.00661 AC: 92 AN: 13910

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

East Asian (EAS) AF: 0.0285 AC: 127 AN: 4450

South Asian (SAS) AF: 0.00525 AC: 23 AN: 4378

European-Finnish (FIN) AF: 0.00688 AC: 65 AN: 9442

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

European-Non Finnish (NFE) AF: 0.00112 AC: 74 AN: 66320

Other (OTH) AF: 0.00653 AC: 13 AN: 1990

⚠️ 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: 0.00114 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.060
Mutation Taster		=100/0	polymorphism

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;