rs41272389

Variant names:

• chr8-132180274-A-G
• rs41272389
• NM_004519.4:c.660T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004519.4(KCNQ3):​c.660T>C​(p.Asn220Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 1,614,106 control chromosomes in the GnomAD database, including 3,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (317 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3359 hom.)
• Consequence: KCNQ3 NM_004519.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.70
• Publications: 7 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 8-132180274-A-G is Benign according to our data. Variant chr8-132180274-A-G is described in ClinVar as Benign. ClinVar VariationId is 129349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0723 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.660T>C	p.Asn220Asn	synonymous	Exon 4 of 15	NP_004510.1
	KCNQ3	NM_001204824.2		c.300T>C	p.Asn100Asn	synonymous	Exon 4 of 15	NP_001191753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.660T>C	p.Asn220Asn	synonymous	Exon 4 of 15	ENSP00000373648.3
	KCNQ3	ENST00000519445.5	TSL:5	c.660T>C	p.Asn220Asn	synonymous	Exon 4 of 15	ENSP00000428790.1
	KCNQ3	ENST00000521134.6	TSL:2	c.300T>C	p.Asn100Asn	synonymous	Exon 4 of 15	ENSP00000429799.1

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7802 AN: 152212 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0524 AC: 13169 AN: 251178 AF XY: 0.0530

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0233

Gnomad ASJ exome AF: 0.0412

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0533

GnomAD4 exome AF: 0.0646 AC: 94422 AN: 1461776 Hom.: 3359 Cov.: 32 AF XY: 0.0633 AC XY: 46033 AN XY: 727178

African (AFR) AF: 0.0126 AC: 422 AN: 33480

American (AMR) AF: 0.0246 AC: 1100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 1041 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0163 AC: 1402 AN: 86258

European-Finnish (FIN) AF: 0.121 AC: 6440 AN: 53324

Middle Eastern (MID) AF: 0.0477 AC: 275 AN: 5766

European-Non Finnish (NFE) AF: 0.0722 AC: 80290 AN: 1111994

Other (OTH) AF: 0.0571 AC: 3449 AN: 60394

GnomAD4 genome AF: 0.0512 AC: 7799 AN: 152330 Hom.: 317 Cov.: 32 AF XY: 0.0518 AC XY: 3860 AN XY: 74486

African (AFR) AF: 0.0152 AC: 632 AN: 41588

American (AMR) AF: 0.0297 AC: 454 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4822

European-Finnish (FIN) AF: 0.125 AC: 1323 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0740 AC: 5033 AN: 68030

Other (OTH) AF: 0.0454 AC: 96 AN: 2114

Alfa AF: 0.0610 Hom.: 197

Bravo AF: 0.0435

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0674

EpiControl AF: 0.0661

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Benign neonatal seizures (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Seizures, benign familial neonatal, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Benign	0.62
PhyloP100		1.7
Mutation Taster		=96/4	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: rs41272389; hg19: chr8-133192521;