rs2436124

Variant names:

• chr8-132122041-G-A
• rs2436124
• NM_004519.4:c.*7221C>T

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.*7221C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,204 control chromosomes in the GnomAD database, including 3,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3755 hom., cov: 32)
  • Exomes 𝑓: 0.23 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.140
• Publications: 2 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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• self-limited familial neonatal epilepsy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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: ClinGen, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-132122041-G-A is Benign according to our data. Variant chr8-132122041-G-A is described in ClinVar as Benign. ClinVar VariationId is 361757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.265 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.*7221C>T		3_prime_UTR	Exon 15 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.*7221C>T		3_prime_UTR	Exon 15 of 15	NP_001191753.1	O43525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.*7221C>T		3_prime_UTR	Exon 15 of 15	ENSP00000373648.3	O43525-1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31392 AN: 152042 Hom.: 3749 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.227 AC: 10 AN: 44 Hom.: 0 Cov.: 0 AF XY: 0.143 AC XY: 4 AN XY: 28

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.375 AC: 6 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.111 AC: 2 AN: 18

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.206 AC: 31402 AN: 152160 Hom.: 3755 Cov.: 32 AF XY: 0.203 AC XY: 15137 AN XY: 74396

African (AFR) AF: 0.120 AC: 4989 AN: 41522

American (AMR) AF: 0.172 AC: 2629 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1024 AN: 3472

East Asian (EAS) AF: 0.00250 AC: 13 AN: 5192

South Asian (SAS) AF: 0.231 AC: 1113 AN: 4814

European-Finnish (FIN) AF: 0.219 AC: 2315 AN: 10588

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18260 AN: 67952

Other (OTH) AF: 0.230 AC: 486 AN: 2114

Alfa AF: 0.230 Hom.: 578

Bravo AF: 0.198

Asia WGS AF: 0.0990 AC: 347 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Benign neonatal seizures (1)
-	-	1	not provided (1)
-	-	1	Seizures, benign familial neonatal, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.1
DANN	Benign	0.78
PhyloP100		-0.14
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: rs2436124; hg19: chr8-133134288;