Genetic Variant KCNA2:c.*9294C>T (chr1-110593989-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 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

Gnomad4 AFR exome

AF:

0.0524

Gnomad4 AMR exome

AF:

0.234

Gnomad4 ASJ exome

AF:

0.0709

Gnomad4 EAS exome

AF:

0.513

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.134

Gnomad4 NFE exome

AF:

0.0607

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.0952

AC:

14477

AN:

152066

Hom.:

1333

Cov.:

AF XY:

0.105

AC XY:

7779

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0510

Gnomad4 AMR

AF:

0.171

Gnomad4 ASJ

AF:

0.0776

Gnomad4 EAS

AF:

0.505

Gnomad4 SAS

AF:

0.174

Gnomad4 FIN

AF:

0.135

Gnomad4 NFE

AF:

0.0637

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0718

Hom.:

116

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

DANN

Benign

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over