rs35413925

Variant names:

• chr8-132172679-G-A
• rs35413925
• NM_004519.4:c.1059C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-132172679-G-A
• chr8-132172679-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004519.4(KCNQ3):​c.1059C>T​(p.Ser353Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,613,508 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (24 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (19 hom.)
• Consequence: KCNQ3 NM_004519.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01
• 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-132172679-G-A is Benign according to our data. Variant chr8-132172679-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00936 (1426/152330) while in subpopulation AFR AF = 0.0327 (1360/41560). AF 95% confidence interval is 0.0313. There are 24 homozygotes in GnomAd4. There are 678 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD 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.1059C>T	p.Ser353Ser	synonymous	Exon 7 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.699C>T	p.Ser233Ser	synonymous	Exon 7 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.1059C>T	p.Ser353Ser	synonymous	Exon 7 of 15	ENSP00000373648.3	O43525-1
	KCNQ3	ENST00000519445.5	TSL:5	c.1059C>T	p.Ser353Ser	synonymous	Exon 7 of 15	ENSP00000428790.1	E7ET42
	KCNQ3	ENST00000521134.6	TSL:2	c.699C>T	p.Ser233Ser	synonymous	Exon 7 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes AF: 0.00934 AC: 1421 AN: 152212 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00212 AC: 531 AN: 250342 AF XY: 0.00159

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000886 AC: 1294 AN: 1461178 Hom.: 19 Cov.: 32 AF XY: 0.000707 AC XY: 514 AN XY: 726936

African (AFR) AF: 0.0338 AC: 1133 AN: 33472

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111908

Other (OTH) AF: 0.00139 AC: 84 AN: 60388

GnomAD4 genome AF: 0.00936 AC: 1426 AN: 152330 Hom.: 24 Cov.: 33 AF XY: 0.00910 AC XY: 678 AN XY: 74494

African (AFR) AF: 0.0327 AC: 1360 AN: 41560

American (AMR) AF: 0.00287 AC: 44 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00486 Hom.: 5

Bravo AF: 0.0103

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Benign neonatal seizures (1)
-	-	1	Inborn genetic diseases (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	-0.76
CADD	Benign	2.6
DANN	Benign	0.70
PhyloP100		-1.0
Mutation Taster		=98/2	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: rs35413925; hg19: chr8-133184926;