Genetic Variant NM_004974.4:c.*1490_*1491insCACACA (chr1-110601792-A-ATGTGTG) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_004974.4(KCNA2):c.*1490_*1491insCACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 1,110,018 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 0.00023 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

KCNA2
NM_004974.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.89

Publications

0 publications found

Variant links:

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

KCNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4 link	c.1490_1491insCACACA		3_prime_UTR_variant	Exon 3 of 3	ENST00000316361.10	NP_004965.1	P16389-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10 link	c.1490_1491insCACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4		P16389-1

Frequencies

GnomAD3 genomes

AF:

0.000229

AC:

AN:

139570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000667

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000709

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000234

Gnomad FIN

AF:

0.000105

Gnomad MID

AF:

0.00662

Gnomad NFE

AF:

0.0000606

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

970350

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

459544

show subpopulations

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

African (AFR)

AF:

0.000152

AC:

AN:

19784

American (AMR)

AF:

0.000145

AC:

AN:

6900

Ashkenazi Jewish (ASJ)

AF:

0.000159

AC:

AN:

12602

East Asian (EAS)

AF:

0.00

AC:

AN:

18534

South Asian (SAS)

AF:

0.000109

AC:

AN:

18318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2554

European-Non Finnish (NFE)

AF:

0.0000167

AC:

AN:

839324

Other (OTH)

AF:

0.0000263

AC:

AN:

38060

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.303

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000229

AC:

AN:

139668

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

67666

show subpopulations

African (AFR)

AF:

0.000664

AC:

AN:

34618

American (AMR)

AF:

0.0000708

AC:

AN:

14122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.00

AC:

AN:

4638

South Asian (SAS)

AF:

0.000234

AC:

AN:

4266

European-Finnish (FIN)

AF:

0.000105

AC:

AN:

9500

Middle Eastern (MID)

AF:

0.00704

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000606

AC:

AN:

65976

Other (OTH)

AF:

0.00

AC:

AN:

1968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Splicing

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

Publications

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NM_004974.4:c.1490_1491insCACACA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over