chr8-132480484-C-A

Variant names:

• chr8-132480484-C-A
• rs1355500787
• NM_004519.4:c.49G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004519.4(KCNQ3):​c.49G>T​(p.Asp17Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D17N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18561551).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.49G>T	p.Asp17Tyr	missense	Exon 1 of 15	NP_004510.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.49G>T	p.Asp17Tyr	missense	Exon 1 of 15	ENSP00000373648.3
	KCNQ3	ENST00000519445.5	TSL:5	c.49G>T	p.Asp17Tyr	missense	Exon 1 of 15	ENSP00000428790.1
	KCNQ3	ENST00000519589.1	TSL:2	n.-174G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149564 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1051724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 502368

African (AFR) AF: 0.00 AC: 0 AN: 21144

American (AMR) AF: 0.00 AC: 0 AN: 7066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11982

East Asian (EAS) AF: 0.00 AC: 0 AN: 22130

South Asian (SAS) AF: 0.00 AC: 0 AN: 20372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2820

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 905978

Other (OTH) AF: 0.00 AC: 0 AN: 40730

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149564 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 72948

African (AFR) AF: 0.00 AC: 0 AN: 41088

American (AMR) AF: 0.00 AC: 0 AN: 15030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67076

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.55
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.045	D
Polyphen		0.0	B
Vest4		0.27
MutPred		0.24		Gain of MoRF binding (P = 0.0891)
MVP		0.59
MPC		1.2
ClinPred		0.088	T
GERP RS		2.8
PromoterAI		-0.015	Neutral
Varity_R		0.15
gMVP		0.37
Mutation Taster		=87/13	polymorphism

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: rs1355500787; hg19: chr8-133492731;