1-110593989-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004974.4(KCNA2):c.*9294C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 1,545,932 control chromosomes in the GnomAD database, including 11,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.095 ( 1333 hom., cov: 30)

Exomes 𝑓: 0.087 ( 10116 hom. )

Consequence

KCNA2
NM_004974.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.795

Publications

3 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 1-110593989-G-A is Benign according to our data. Variant chr1-110593989-G-A is described in ClinVar as [Benign]. Clinvar id is 1257086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4 link	c.*9294C>T		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.*9294C>T		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4		P16389-1

Frequencies

GnomAD3 genomes

AF:

0.0953

AC:

14474

AN:

151948

Hom.:

1333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0510

Gnomad AMI

AF:

0.0573

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.0776

Gnomad EAS

AF:

0.505

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.135

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0637

Gnomad OTH

AF:

0.103

GnomAD4 exome

AF:

0.0868

AC:

120964

AN:

1393866

Hom.:

10116

Cov.:

AF XY:

0.0887

AC XY:

60978

AN XY:

687442

show subpopulations

African (AFR)

AF:

0.0524

AC:

1648

AN:

31434

American (AMR)

AF:

0.234

AC:

8224

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.0709

AC:

1772

AN:

25008

East Asian (EAS)

AF:

0.513

AC:

18174

AN:

35436

South Asian (SAS)

AF:

0.167

AC:

13114

AN:

78488

European-Finnish (FIN)

AF:

0.134

AC:

6395

AN:

47748

Middle Eastern (MID)

AF:

0.0698

AC:

397

AN:

5688

European-Non Finnish (NFE)

AF:

0.0607

AC:

65347

AN:

1077026

Other (OTH)

AF:

0.102

AC:

5893

AN:

57836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

4811

9622

14434

19245

24056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0952

AC:

14477

AN:

152066

Hom.:

1333

Cov.:

AF XY:

0.105

AC XY:

7779

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0510

AC:

2116

AN:

41490

American (AMR)

AF:

0.171

AC:

2604

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0776

AC:

269

AN:

3468

East Asian (EAS)

AF:

0.505

AC:

2611

AN:

5168

South Asian (SAS)

AF:

0.174

AC:

839

AN:

4820

European-Finnish (FIN)

AF:

0.135

AC:

1426

AN:

10560

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0637

AC:

4331

AN:

67990

Other (OTH)

AF:

0.102

AC:

214

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

599

1197

1796

2394

2993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0853

Hom.:

523

Bravo

AF:

0.0994

Asia WGS

AF:

0.301

AC:

1043

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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1-110593989-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over