1-110593985-C-T

Variant names:

• chr1-110593985-C-T
• rs12096011
• NM_004974.4:c.*9298G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004974.4(KCNA2):​c.*9298G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,547,722 control chromosomes in the GnomAD database, including 1,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (750 hom., cov: 30)
  • Exomes 𝑓: 0.0055 (644 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.52
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 1-110593985-C-T is Benign according to our data. Variant chr1-110593985-C-T is described in ClinVar as [Benign]. Clinvar id is 1237563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*9298G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000316361.10	NP_004965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10	c.*9298G>A		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8058 AN: 152086 Hom.: 746 Cov.: 30

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.00546 AC: 7620 AN: 1395518 Hom.: 644 Cov.: 30 AF XY: 0.00473 AC XY: 3259 AN XY: 688306

African (AFR) AF: 0.192 AC: 6053 AN: 31458

American (AMR) AF: 0.00952 AC: 337 AN: 35388

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25078

East Asian (EAS) AF: 0.00 AC: 0 AN: 35584

South Asian (SAS) AF: 0.000470 AC: 37 AN: 78704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47946

Middle Eastern (MID) AF: 0.00791 AC: 45 AN: 5688

European-Non Finnish (NFE) AF: 0.000361 AC: 389 AN: 1077772

Other (OTH) AF: 0.0131 AC: 758 AN: 57900

GnomAD4 genome AF: 0.0531 AC: 8078 AN: 152204 Hom.: 750 Cov.: 30 AF XY: 0.0513 AC XY: 3818 AN XY: 74436

African (AFR) AF: 0.184 AC: 7650 AN: 41484

American (AMR) AF: 0.0190 AC: 290 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68016

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0185 Hom.: 251

Bravo AF: 0.0601

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.78
PhyloP100		3.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12096011; hg19: chr1-111136607;