1-110601828-G-GTGTGTA

Variant names:

• chr1-110601828-G-GTGTGTA
• rs763912060
• NM_004974.4:c.*1454_*1455insTACACA

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_*1455insTACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,230,850 control chromosomes in the GnomAD database, including 54 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 28)
  • Exomes 𝑓: 0.0030 (8 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-GTGTGTA is Benign according to our data. Variant chr1-110601828-G-GTGTGTA is described in ClinVar as [Likely_benign]. Clinvar id is 1200267.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_*1455insTACACA		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_*1455insTACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2001 AN: 143204 Hom.: 46 Cov.: 28

Gnomad AFR AF: 0.00656

Gnomad AMI AF: 0.00668

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.00938

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00296

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.0157

GnomAD4 exome AF: 0.00300 AC: 3264 AN: 1087566 Hom.: 8 Cov.: 27 AF XY: 0.00314 AC XY: 1638 AN XY: 521892

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

African (AFR) AF: 0.00195 AC: 44 AN: 22514

American (AMR) AF: 0.0357 AC: 373 AN: 10458

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 84 AN: 15914

East Asian (EAS) AF: 0.0480 AC: 1063 AN: 22154

South Asian (SAS) AF: 0.00319 AC: 114 AN: 35774

European-Finnish (FIN) AF: 0.00557 AC: 125 AN: 22444

Middle Eastern (MID) AF: 0.00392 AC: 12 AN: 3064

European-Non Finnish (NFE) AF: 0.00140 AC: 1273 AN: 910604

Other (OTH) AF: 0.00394 AC: 176 AN: 44640

⚠️ 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: 0.0140 AC: 2012 AN: 143284 Hom.: 46 Cov.: 28 AF XY: 0.0148 AC XY: 1024 AN XY: 69356

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

African (AFR) AF: 0.00675 AC: 259 AN: 38348

American (AMR) AF: 0.0469 AC: 650 AN: 13848

Ashkenazi Jewish (ASJ) AF: 0.00938 AC: 32 AN: 3412

East Asian (EAS) AF: 0.0726 AC: 322 AN: 4438

South Asian (SAS) AF: 0.0213 AC: 93 AN: 4372

European-Finnish (FIN) AF: 0.00296 AC: 28 AN: 9466

Middle Eastern (MID) AF: 0.0104 AC: 3 AN: 288

European-Non Finnish (NFE) AF: 0.00889 AC: 589 AN: 66220

Other (OTH) AF: 0.0150 AC: 30 AN: 1994

⚠️ 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: 0.000802 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 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;