rs115258190

chr1-110602079-G-Achr1-110602079-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000369770.7(KCNA2):c.986C>T(p.Ala329Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,550,478 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: KCNA2 ENST00000369770.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.717

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNA2
• BP4: Computational evidence support a benign effect (MetaRNN=0.00828144).
• BP6: Variant 1-110602079-G-A is Benign according to our data. Variant chr1-110602079-G-A is described in ClinVar as [Benign]. Clinvar id is 586061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00273 (416/152200) while in subpopulation AFR AF= 0.00954 (396/41510). AF 95% confidence interval is 0.00876. There are 4 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA2	NM_004974.4	c.*1204C>T		3_prime_UTR_variant	3/3	ENST00000316361.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA2	ENST00000316361.10	c.*1204C>T		3_prime_UTR_variant	3/3	2	NM_004974.4	P1

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 410 AN: 152082 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000570 AC: 85 AN: 149236 Hom.: 0 AF XY: 0.000498 AC XY: 40 AN XY: 80386

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000928

Gnomad SAS exome AF: 0.000710

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000695

GnomAD4 exome AF: 0.000326 AC: 456 AN: 1398278 Hom.: 2 Cov.: 34 AF XY: 0.000331 AC XY: 228 AN XY: 689658

Gnomad4 AFR exome AF: 0.00997

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000682

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000482

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152200 Hom.: 4 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74426

Gnomad4 AFR AF: 0.00954

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00309

ExAC AF: 0.000993 AC: 20

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.78
Dann	Uncertain	0.98
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	2.6	N;.
REVEL	Benign	0.23
Sift	Uncertain	0.011	D;.
Sift4G	Benign	0.47	T;.
Vest4		0.10
MVP		0.73
ClinPred		0.035	T
GERP RS		-2.9

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

Other links and lift over

dbSNP: rs115258190; hg19: chr1-111144701; COSMIC: COSV60371395; COSMIC: COSV60371395;