rs796052676

Variant names:

• chr8-132180246-G-A
• rs796052676
• NM_004519.4:c.688C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-132180246-G-A
• chr8-132180246-G-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004519.4(KCNQ3):​c.688C>T​(p.Arg230Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000241571: Published functional studies demonstrate a gain-of-function stabilization of the ion channel's activated state (Miceli et al., 2015)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:2
• Conservation: PhyloP100: 6.79
• Publications: 30 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000241571: Published functional studies demonstrate a gain-of-function stabilization of the ion channel's activated state (Miceli et al., 2015); SCV002034857: In vitro analyses have demonstrated that this variant, which affects a crucial gating residue in the S4 transmembrane segment, stabilizes the activated state of the channel, allowing current to flow throughout the physiological voltage range and resulting in gain of function (Miceli et al. 2015; Barro-Soria 2019; Sands et al. 2019).; SCV001206243: Experimental studies have shown that this missense change affects KCNQ3 function (PMID: 25740509, 30578330).; SCV005399917: "Many functional analyses on this variant, R230C, have shown that this is a crucial gating residue in the S4 transmembrane segment where the variant stabilises the activated state of the channel, resulting in a gain of function effect (PMIDs: 31177578, 30578330, 25740509)."; SCV001441367: "functional studies indicate that it causes a gain-of-function stabilization of the ion channel's activated state" [PMID: 31177578; PMID: 25740509]
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004519.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-132180245-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 424397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 8-132180246-G-A is Pathogenic according to our data. Variant chr8-132180246-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 205963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.688C>T	p.Arg230Cys	missense	Exon 4 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.328C>T	p.Arg110Cys	missense	Exon 4 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.688C>T	p.Arg230Cys	missense	Exon 4 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.688C>T	p.Arg230Cys	missense	Exon 4 of 15	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000521134.6	TSL:2	c.328C>T	p.Arg110Cys	missense	Exon 4 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Seizures, benign familial neonatal, 2 (11)
3	-	-	not provided (3)
2	-	-	Intellectual disability (2)
1	-	-	Benign neonatal seizures (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	KCNQ3-related Autism and developmental disability (1)
1	-	-	KCNQ3-related developmental disability (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Seizures, benign familial infantile, 5 (1)
1	-	-	Severe intellectual disability (1)
1	-	-	Severe neurodevelopmental delay (1)
-	-	-	Benign neonatal seizures;C0238111:Lennox-Gastaut syndrome;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of MoRF binding (P = 0.0045)
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.98
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs796052676; hg19: chr8-133192493; COSMIC: COSV66466182;