rs78349687

chr1-110603598-C-Gchr1-110603598-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004974.4(KCNA2):c.1185G>C(p.Ala395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,613,908 control chromosomes in the GnomAD database, including 2,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A395A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.044 (192 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2340 hom.)
• Consequence: KCNA2 NM_004974.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.177

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-110603598-C-G is Benign according to our data. Variant chr1-110603598-C-G is described in ClinVar as [Benign]. Clinvar id is 447615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.177 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA2	NM_004974.4	c.1185G>C	p.Ala395=	synonymous_variant	3/3	ENST00000316361.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA2	ENST00000316361.10	c.1185G>C	p.Ala395=	synonymous_variant	3/3	2	NM_004974.4	P1

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6663 AN: 152034 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0897

Gnomad FIN AF: 0.0912

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0523

Gnomad OTH AF: 0.0382

GnomAD3 exomes AF: 0.0529 AC: 13302 AN: 251392 Hom.: 533 AF XY: 0.0561 AC XY: 7617 AN XY: 135872

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0902

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0534

Gnomad OTH exome AF: 0.0611

GnomAD4 exome AF: 0.0514 AC: 75116 AN: 1461756 Hom.: 2340 Cov.: 34 AF XY: 0.0529 AC XY: 38504 AN XY: 727192

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.0234

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0901

Gnomad4 FIN exome AF: 0.0900

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0525

GnomAD4 genome AF: 0.0439 AC: 6672 AN: 152152 Hom.: 192 Cov.: 32 AF XY: 0.0461 AC XY: 3427 AN XY: 74378

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0902

Gnomad4 FIN AF: 0.0912

Gnomad4 NFE AF: 0.0523

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0454 Hom.: 76

Bravo AF: 0.0371

Asia WGS AF: 0.0510 AC: 175 AN: 3478

EpiCase AF: 0.0582

EpiControl AF: 0.0537

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 22, 2017

- -

Developmental and epileptic encephalopathy, 32 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.91
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs78349687; hg19: chr1-111146220; COSMIC: COSV60369493;