1-110601792-A-G

Variant names:

• chr1-110601792-A-G
• rs111728011
• NM_004974.4:c.*1491T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004974.4(KCNA2):​c.*1491T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 138,166 control chromosomes in the GnomAD database, including 1,162 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1162 hom., cov: 27)
  • Exomes 𝑓: 0.028 (1945 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0400
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 1-110601792-A-G is Benign according to our data. Variant chr1-110601792-A-G is described in ClinVar as [Benign]. Clinvar id is 1289753.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1491T>C		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.*1491T>C		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.105 AC: 14547 AN: 138066 Hom.: 1150 Cov.: 27

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0558

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0530

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.112

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0284 AC: 26952 AN: 949996 Hom.: 1945 Cov.: 21 AF XY: 0.0289 AC XY: 13019 AN XY: 449938

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

African (AFR) AF: 0.0413 AC: 796 AN: 19290

American (AMR) AF: 0.234 AC: 1568 AN: 6712

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 496 AN: 12458

East Asian (EAS) AF: 0.340 AC: 6078 AN: 17884

South Asian (SAS) AF: 0.0422 AC: 737 AN: 17456

European-Finnish (FIN) AF: 0.0850 AC: 1207 AN: 14202

Middle Eastern (MID) AF: 0.0290 AC: 73 AN: 2514

European-Non Finnish (NFE) AF: 0.0176 AC: 14444 AN: 822328

Other (OTH) AF: 0.0418 AC: 1553 AN: 37152

⚠️ 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: 0.105 AC: 14575 AN: 138166 Hom.: 1162 Cov.: 27 AF XY: 0.113 AC XY: 7540 AN XY: 66852

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

African (AFR) AF: 0.102 AC: 3476 AN: 34162

American (AMR) AF: 0.258 AC: 3576 AN: 13878

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 216 AN: 3392

East Asian (EAS) AF: 0.361 AC: 1627 AN: 4504

South Asian (SAS) AF: 0.157 AC: 656 AN: 4188

European-Finnish (FIN) AF: 0.101 AC: 945 AN: 9380

Middle Eastern (MID) AF: 0.0528 AC: 15 AN: 284

European-Non Finnish (NFE) AF: 0.0580 AC: 3801 AN: 65560

Other (OTH) AF: 0.110 AC: 214 AN: 1940

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0329 Hom.: 17

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	1.9
DANN	Benign	0.39
PhyloP100		-0.040
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: rs111728011; hg19: chr1-111144414;