1-110601828-G-A

Variant names:

• chr1-110601828-G-A
• rs6675561
• NM_004974.4:c.*1455C>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.*1455C>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 0.0161 in 1,235,860 control chromosomes in the GnomAD database, including 1,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.065 (1072 hom., cov: 27)
  • Exomes 𝑓: 0.0097 (587 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.312
• Publications: 1 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=-0.97).
• BP6: Variant 1-110601828-G-A is Benign according to our data. Variant chr1-110601828-G-A is described in ClinVar as [Benign]. Clinvar id is 1246346.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1455C>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.*1455C>T		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9329 AN: 143378 Hom.: 1066 Cov.: 27

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.00409

Gnomad EAS AF: 0.00244

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000422

Gnomad MID AF: 0.0390

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0501

GnomAD4 exome AF: 0.00965 AC: 10545 AN: 1092408 Hom.: 587 Cov.: 25 AF XY: 0.00887 AC XY: 4648 AN XY: 524112

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

African (AFR) AF: 0.222 AC: 4827 AN: 21750

American (AMR) AF: 0.0236 AC: 253 AN: 10706

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 74 AN: 15982

East Asian (EAS) AF: 0.00991 AC: 225 AN: 22696

South Asian (SAS) AF: 0.00828 AC: 298 AN: 36002

European-Finnish (FIN) AF: 0.00271 AC: 61 AN: 22472

Middle Eastern (MID) AF: 0.0163 AC: 50 AN: 3074

European-Non Finnish (NFE) AF: 0.00427 AC: 3910 AN: 914966

Other (OTH) AF: 0.0189 AC: 847 AN: 44760

⚠️ 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: 0.0652 AC: 9358 AN: 143452 Hom.: 1072 Cov.: 27 AF XY: 0.0633 AC XY: 4396 AN XY: 69460

African (AFR) AF: 0.228 AC: 8704 AN: 38232

American (AMR) AF: 0.0273 AC: 380 AN: 13932

Ashkenazi Jewish (ASJ) AF: 0.00409 AC: 14 AN: 3420

East Asian (EAS) AF: 0.00245 AC: 11 AN: 4498

South Asian (SAS) AF: 0.00228 AC: 10 AN: 4392

European-Finnish (FIN) AF: 0.000422 AC: 4 AN: 9470

Middle Eastern (MID) AF: 0.0417 AC: 12 AN: 288

European-Non Finnish (NFE) AF: 0.00187 AC: 124 AN: 66330

Other (OTH) AF: 0.0497 AC: 99 AN: 1992

Alfa AF: 0.00125 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 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	-0.97
CADD	Benign	0.33
DANN	Benign	0.16
PhyloP100		0.31
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: rs6675561; hg19: chr1-111144450;