1-110593843-G-C

Variant names:

• chr1-110593843-G-C
• rs569128112
• NM_004974.4:c.*9440C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004974.4(KCNA2):​c.*9440C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,548,694 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.03
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-110593843-G-C is Benign according to our data. Variant chr1-110593843-G-C is described in ClinVar as [Benign]. Clinvar id is 1262436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 129 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*9440C>G		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.*9440C>G		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152174 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000604 AC: 89 AN: 147276 AF XY: 0.000630

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000167

Gnomad ASJ exome AF: 0.000240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000361

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.000471

GnomAD4 exome AF: 0.00133 AC: 1863 AN: 1396520 Hom.: 4 Cov.: 30 AF XY: 0.00127 AC XY: 878 AN XY: 688716

African (AFR) AF: 0.000285 AC: 9 AN: 31568

American (AMR) AF: 0.000225 AC: 8 AN: 35478

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 35668

South Asian (SAS) AF: 0.00 AC: 0 AN: 78834

European-Finnish (FIN) AF: 0.000436 AC: 21 AN: 48118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00164 AC: 1767 AN: 1078118

Other (OTH) AF: 0.000932 AC: 54 AN: 57922

GnomAD4 genome AF: 0.000848 AC: 129 AN: 152174 Hom.: 0 Cov.: 30 AF XY: 0.000901 AC XY: 67 AN XY: 74342

African (AFR) AF: 0.000217 AC: 9 AN: 41432

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68022

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000929

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 06, 2021

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	-0.51
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		3.0
Mutation Taster		=100/0	polymorphism

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: rs569128112; hg19: chr1-111136465;