1-110601798-G-A

Variant names:

• chr1-110601798-G-A
• rs867303897
• NM_004974.4:c.*1485C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004974.4(KCNA2):​c.*1485C>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 0.0105 in 939,776 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (283 hom., cov: 27)
  • Exomes 𝑓: 0.0056 (7 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.548
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-110601798-G-A is Benign according to our data. Variant chr1-110601798-G-A is described in ClinVar as [Benign]. Clinvar id is 1237517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1485C>T		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.*1485C>T		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 5278 AN: 129080 Hom.: 284 Cov.: 27

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00123

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.000984

Gnomad MID AF: 0.0408

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.0323

GnomAD4 exome AF: 0.00563 AC: 4561 AN: 810604 Hom.: 7 Cov.: 18 AF XY: 0.00548 AC XY: 2109 AN XY: 384794

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.110 AC: 1722 AN: 15670

American (AMR) AF: 0.00660 AC: 49 AN: 7420

Ashkenazi Jewish (ASJ) AF: 0.00164 AC: 17 AN: 10348

East Asian (EAS) AF: 0.000410 AC: 8 AN: 19528

South Asian (SAS) AF: 0.00178 AC: 33 AN: 18534

European-Finnish (FIN) AF: 0.00233 AC: 29 AN: 12430

Middle Eastern (MID) AF: 0.0138 AC: 30 AN: 2176

European-Non Finnish (NFE) AF: 0.00343 AC: 2374 AN: 692760

Other (OTH) AF: 0.00942 AC: 299 AN: 31738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0409 AC: 5284 AN: 129172 Hom.: 283 Cov.: 27 AF XY: 0.0399 AC XY: 2523 AN XY: 63246

African (AFR) AF: 0.142 AC: 4683 AN: 33002

American (AMR) AF: 0.0206 AC: 269 AN: 13032

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 4 AN: 3242

East Asian (EAS) AF: 0.00 AC: 0 AN: 4538

South Asian (SAS) AF: 0.00146 AC: 6 AN: 4112

European-Finnish (FIN) AF: 0.000984 AC: 9 AN: 9148

Middle Eastern (MID) AF: 0.0438 AC: 12 AN: 274

European-Non Finnish (NFE) AF: 0.00410 AC: 243 AN: 59240

Other (OTH) AF: 0.0319 AC: 58 AN: 1816

Alfa AF: 0.0343 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.47
PhyloP100		-0.55
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: rs867303897; hg19: chr1-111144420;