1-110601788-A-G

Variant names:

• chr1-110601788-A-G
• rs1403613919
• NM_004974.4:c.*1495T>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.*1495T>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 0.00551 in 138,228 control chromosomes in the GnomAD database, including 5 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 30)
  • Exomes 𝑓: 0.00059 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.523
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-110601788-A-G is Benign according to our data. Variant chr1-110601788-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1192746.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.*1495T>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.*1495T>C		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 755 AN: 138142 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00960

Gnomad ASJ AF: 0.00557

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.00697

Gnomad FIN AF: 0.000620

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000762

Gnomad OTH AF: 0.00780

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000586 AC: 611 AN: 1041860 Hom.: 1 Cov.: 24 AF XY: 0.000584 AC XY: 288 AN XY: 493198

African (AFR) AF: 0.00322 AC: 70 AN: 21768

American (AMR) AF: 0.00901 AC: 75 AN: 8328

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 22 AN: 13646

East Asian (EAS) AF: 0.00879 AC: 188 AN: 21376

South Asian (SAS) AF: 0.00162 AC: 32 AN: 19760

European-Finnish (FIN) AF: 0.000686 AC: 11 AN: 16030

Middle Eastern (MID) AF: 0.00251 AC: 7 AN: 2784

European-Non Finnish (NFE) AF: 0.000173 AC: 155 AN: 897038

Other (OTH) AF: 0.00124 AC: 51 AN: 41130

GnomAD4 genome AF: 0.00551 AC: 762 AN: 138228 Hom.: 5 Cov.: 30 AF XY: 0.00535 AC XY: 359 AN XY: 67110

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

African (AFR) AF: 0.0128 AC: 423 AN: 33046

American (AMR) AF: 0.00959 AC: 137 AN: 14290

Ashkenazi Jewish (ASJ) AF: 0.00557 AC: 19 AN: 3414

East Asian (EAS) AF: 0.0170 AC: 82 AN: 4822

South Asian (SAS) AF: 0.00697 AC: 30 AN: 4302

European-Finnish (FIN) AF: 0.000620 AC: 6 AN: 9670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000762 AC: 50 AN: 65604

Other (OTH) AF: 0.00772 AC: 15 AN: 1944

⚠️ 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: 0.00331 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

GeneDx

Significance: Likely 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	-0.86
CADD	Benign	1.5
DANN	Benign	0.74
PhyloP100		-0.52

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: rs1403613919; hg19: chr1-111144410;