1-110601828-G-GTGTGTGTA

Variant names:

• chr1-110601828-G-GTGTGTGTA
• rs763912060
• NM_004974.4:c.*1454_*1455insTACACACA

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_*1455insTACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 142,244 control chromosomes in the GnomAD database, including 221 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (221 hom., cov: 28)
  • Exomes 𝑓: 0.0051 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: 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-GTGTGTGTA is Benign according to our data. Variant chr1-110601828-G-GTGTGTGTA is described in ClinVar as [Benign]. Clinvar id is 1247502.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_*1455insTACACACA		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_*1455insTACACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 5866 AN: 142166 Hom.: 218 Cov.: 28

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.0839

Gnomad SAS AF: 0.0611

Gnomad FIN AF: 0.0480

Gnomad MID AF: 0.0296

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0467

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00506 AC: 5505 AN: 1087838 Hom.: 12 Cov.: 27 AF XY: 0.00539 AC XY: 2814 AN XY: 521930

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

African (AFR) AF: 0.00654 AC: 146 AN: 22332

American (AMR) AF: 0.0598 AC: 611 AN: 10214

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 165 AN: 15902

East Asian (EAS) AF: 0.0577 AC: 1277 AN: 22136

South Asian (SAS) AF: 0.00465 AC: 166 AN: 35708

European-Finnish (FIN) AF: 0.0219 AC: 486 AN: 22212

Middle Eastern (MID) AF: 0.00851 AC: 26 AN: 3056

European-Non Finnish (NFE) AF: 0.00249 AC: 2267 AN: 911690

Other (OTH) AF: 0.00810 AC: 361 AN: 44588

⚠️ 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: 0.0413 AC: 5874 AN: 142244 Hom.: 221 Cov.: 28 AF XY: 0.0445 AC XY: 3062 AN XY: 68786

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

African (AFR) AF: 0.0247 AC: 942 AN: 38162

American (AMR) AF: 0.136 AC: 1855 AN: 13614

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 128 AN: 3392

East Asian (EAS) AF: 0.0834 AC: 367 AN: 4398

South Asian (SAS) AF: 0.0610 AC: 264 AN: 4330

European-Finnish (FIN) AF: 0.0480 AC: 448 AN: 9342

Middle Eastern (MID) AF: 0.0317 AC: 9 AN: 284

European-Non Finnish (NFE) AF: 0.0262 AC: 1727 AN: 65850

Other (OTH) AF: 0.0469 AC: 93 AN: 1982

⚠️ 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: 0.0178 Hom.: 10

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: 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;