rs11785257

Variant names:

• chr8-132121756-G-A
• rs11785257
• NM_004519.4:c.*7506C>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.*7506C>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 0.143 in 152,190 control chromosomes in the GnomAD database, including 1,693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1693 hom., cov: 32)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.20
• Publications: 1 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 8-132121756-G-A is Benign according to our data. Variant chr8-132121756-G-A is described in ClinVar as Benign. ClinVar VariationId is 361750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 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.*7506C>T		3_prime_UTR	Exon 15 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.*7506C>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.*7506C>T		3_prime_UTR	Exon 15 of 15	ENSP00000373648.3	O43525-1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21748 AN: 152056 Hom.: 1694 Cov.: 32

Gnomad AFR AF: 0.0985

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0840

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0625 AC: 1 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0714 AC: 1 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.143 AC: 21765 AN: 152174 Hom.: 1693 Cov.: 32 AF XY: 0.146 AC XY: 10865 AN XY: 74376

African (AFR) AF: 0.0987 AC: 4100 AN: 41544

American (AMR) AF: 0.128 AC: 1956 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3468

East Asian (EAS) AF: 0.166 AC: 861 AN: 5178

South Asian (SAS) AF: 0.0841 AC: 405 AN: 4816

European-Finnish (FIN) AF: 0.230 AC: 2433 AN: 10582

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11130 AN: 67992

Other (OTH) AF: 0.126 AC: 266 AN: 2108

Alfa AF: 0.159 Hom.: 257

Bravo AF: 0.134

Asia WGS AF: 0.121 AC: 421 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	0.51
DANN	Benign	0.64
PhyloP100		-1.2
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: rs11785257; hg19: chr8-133134003;