rs74582884

Variant names:

• chr8-132134369-G-A
• rs74582884
• NM_004519.4:c.1720C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-132134369-G-A
• chr8-132134369-G-T
• chr8-132134369-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004519.4(KCNQ3):​c.1720C>T​(p.Pro574Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,612,916 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P574T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 9.32
• Publications: 27 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: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01873827).
• BP6: Variant 8-132134369-G-A is Benign according to our data. Variant chr8-132134369-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00246 (374/152208) while in subpopulation AMR AF = 0.0053 (81/15282). AF 95% confidence interval is 0.00437. There are 4 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.1720C>T	p.Pro574Ser	missense	Exon 13 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.1360C>T	p.Pro454Ser	missense	Exon 13 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.1720C>T	p.Pro574Ser	missense	Exon 13 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.1720C>T	p.Pro574Ser	missense	Exon 13 of 15	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000521134.6	TSL:2	c.1360C>T	p.Pro454Ser	missense	Exon 13 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152090 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00212 AC: 534 AN: 251432 AF XY: 0.00206

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00277 AC: 4049 AN: 1460708 Hom.: 9 Cov.: 30 AF XY: 0.00274 AC XY: 1990 AN XY: 726748

African (AFR) AF: 0.000926 AC: 31 AN: 33468

American (AMR) AF: 0.00262 AC: 117 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86216

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5754

European-Non Finnish (NFE) AF: 0.00332 AC: 3684 AN: 1110956

Other (OTH) AF: 0.00263 AC: 159 AN: 60354

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152208 Hom.: 4 Cov.: 31 AF XY: 0.00253 AC XY: 188 AN XY: 74412

African (AFR) AF: 0.000626 AC: 26 AN: 41554

American (AMR) AF: 0.00530 AC: 81 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00366 AC: 249 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00331 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00199 AC: 242

EpiCase AF: 0.00393

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Seizures, benign familial neonatal, 2 (5)
-	-	3	not specified (3)
-	-	1	Benign Neonatal Epilepsy (1)
-	-	1	Benign neonatal seizures (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	KCNQ3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.019	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.83
Sift	Benign	0.11	T
Sift4G	Benign	0.092	T
Polyphen		1.0	D
Vest4		0.67
MVP		0.89
MPC		0.51
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.65
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs74582884; hg19: chr8-133146616;