rs2469515

Variant names:

• chr8-132137856-C-T
• rs2469515
• NM_004519.4:c.1700+29G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004519.4(KCNQ3):​c.1700+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,610,908 control chromosomes in the GnomAD database, including 35,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2567 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32992 hom.)
• Consequence: KCNQ3 NM_004519.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.907
• Publications: 8 publications found

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 Gene-Disease associations (from GenCC):

• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-132137856-C-T is Benign according to our data. Variant chr8-132137856-C-T is described in ClinVar as Benign. ClinVar VariationId is 670883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004519.4. 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
	KCNQ3	NM_004519.4	MANE Select	c.1700+29G>A		intron	N/A	NP_004510.1
	KCNQ3	NM_001204824.2		c.1340+29G>A		intron	N/A	NP_001191753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.1700+29G>A		intron	N/A	ENSP00000373648.3
	KCNQ3	ENST00000519445.5	TSL:5	c.1700+29G>A		intron	N/A	ENSP00000428790.1
	KCNQ3	ENST00000521134.6	TSL:2	c.1340+29G>A		intron	N/A	ENSP00000429799.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25425 AN: 152088 Hom.: 2565 Cov.: 32

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.169 AC: 42367 AN: 250910 AF XY: 0.176

Gnomad AFR exome AF: 0.0812

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.00832

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.205 AC: 299635 AN: 1458702 Hom.: 32992 Cov.: 32 AF XY: 0.205 AC XY: 149047 AN XY: 725854

African (AFR) AF: 0.0805 AC: 2690 AN: 33418

American (AMR) AF: 0.118 AC: 5274 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5807 AN: 26114

East Asian (EAS) AF: 0.00867 AC: 344 AN: 39678

South Asian (SAS) AF: 0.155 AC: 13399 AN: 86202

European-Finnish (FIN) AF: 0.159 AC: 8445 AN: 53002

Middle Eastern (MID) AF: 0.272 AC: 1566 AN: 5756

European-Non Finnish (NFE) AF: 0.225 AC: 250142 AN: 1109530

Other (OTH) AF: 0.199 AC: 11968 AN: 60288

GnomAD4 genome AF: 0.167 AC: 25422 AN: 152206 Hom.: 2567 Cov.: 32 AF XY: 0.164 AC XY: 12184 AN XY: 74420

African (AFR) AF: 0.0855 AC: 3553 AN: 41558

American (AMR) AF: 0.153 AC: 2331 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 788 AN: 3472

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5180

South Asian (SAS) AF: 0.152 AC: 735 AN: 4826

European-Finnish (FIN) AF: 0.161 AC: 1701 AN: 10592

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15350 AN: 67976

Other (OTH) AF: 0.196 AC: 415 AN: 2116

Alfa AF: 0.212 Hom.: 6960

Bravo AF: 0.163

Asia WGS AF: 0.0790 AC: 273 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)
-	-	1	Seizures, benign familial neonatal, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.65
DANN	Benign	0.66
PhyloP100		-0.91
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: rs2469515; hg19: chr8-133150103;