1-110601904-T-G

Variant names:

• chr1-110601904-T-G
• rs4839071
• NM_004974.4:c.*1379A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004974.4(KCNA2):​c.*1379A>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 1 in 1,455,914 control chromosomes in the GnomAD database, including 727,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75688 hom., cov: 28)
  • Exomes 𝑓: 1.0 (651799 hom.)
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.52
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 1-110601904-T-G is Benign according to our data. Variant chr1-110601904-T-G is described in ClinVar as Benign. ClinVar VariationId is 1284086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA2	NM_004974.4	MANE Select	c.*1379A>C		3_prime_UTR	Exon 3 of 3	NP_004965.1	P16389-1
	KCNA2	NM_001204269.2		c.1035+126A>C		intron	N/A	NP_001191198.1	P16389-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA2	ENST00000316361.10	TSL:2 MANE Select	c.*1379A>C		3_prime_UTR	Exon 3 of 3	ENSP00000314520.4	P16389-1
	KCNA2	ENST00000369770.7	TSL:1	c.1035+126A>C		intron	N/A	ENSP00000358785.3	P16389-2
	KCNA2	ENST00000633222.1	TSL:5	c.*1379A>C		3_prime_UTR	Exon 3 of 3	ENSP00000487785.1	P16389-1

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151511 AN: 151764 Hom.: 75629 Cov.: 28

Gnomad AFR AF: 0.994

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1303815 AN: 1304032 Hom.: 651799 Cov.: 40 AF XY: 1.00 AC XY: 633165 AN XY: 633262

African (AFR) AF: 0.994 AC: 29007 AN: 29192

American (AMR) AF: 1.00 AC: 25811 AN: 25812

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 20198 AN: 20198

East Asian (EAS) AF: 1.00 AC: 35012 AN: 35012

South Asian (SAS) AF: 1.00 AC: 65004 AN: 65004

European-Finnish (FIN) AF: 1.00 AC: 31582 AN: 31582

Middle Eastern (MID) AF: 0.999 AC: 3778 AN: 3780

European-Non Finnish (NFE) AF: 1.00 AC: 1039174 AN: 1039178

Other (OTH) AF: 1.00 AC: 54249 AN: 54274

GnomAD4 genome AF: 0.998 AC: 151629 AN: 151882 Hom.: 75688 Cov.: 28 AF XY: 0.998 AC XY: 74116 AN XY: 74240

African (AFR) AF: 0.994 AC: 41087 AN: 41334

American (AMR) AF: 1.00 AC: 15253 AN: 15258

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 1.00 AC: 4785 AN: 4786

European-Finnish (FIN) AF: 1.00 AC: 10562 AN: 10562

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68002 AN: 68002

Other (OTH) AF: 1.00 AC: 2100 AN: 2100

Alfa AF: 1.00 Hom.: 3328

Bravo AF: 0.998

Asia WGS AF: 0.999 AC: 3476 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.84
PhyloP100		3.5
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: rs4839071; hg19: chr1-111144526;