rs147274045

Variant names:

• chr20-63406719-C-T
• rs147274045
• NM_172107.4:c.2544G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63406719-C-T
• chr20-63406719-C-A

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_172107.4(KCNQ2):​c.2544G>A​(p.Pro848Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,606,460 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (16 hom.)
• Consequence: KCNQ2 NM_172107.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.54
• Publications: 0 publications found

Genes affected

KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNQ2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• neonatal encephalopathy with non-epileptic myoclonus

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neonatal-onset developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-63406719-C-T is Benign according to our data. Variant chr20-63406719-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00258 (393/152364) while in subpopulation NFE AF = 0.00397 (270/68034). AF 95% confidence interval is 0.00358. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 393 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172107.4. 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
	KCNQ2	NM_172107.4	MANE Select	c.2544G>A	p.Pro848Pro	synonymous	Exon 17 of 17	NP_742105.1	O43526-1
	KCNQ2	NM_001382235.1		c.2598G>A	p.Pro866Pro	synonymous	Exon 17 of 17	NP_001369164.1	A0A9L9PXL0
	KCNQ2	NM_172106.3		c.2490G>A	p.Pro830Pro	synonymous	Exon 16 of 16	NP_742104.1	O43526-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.2544G>A	p.Pro848Pro	synonymous	Exon 17 of 17	ENSP00000352035.2	O43526-1
	KCNQ2	ENST00000626839.2	TSL:1	c.2490G>A	p.Pro830Pro	synonymous	Exon 16 of 16	ENSP00000486706.1	O43526-2
	KCNQ2	ENST00000344462.8	TSL:1	c.2451G>A	p.Pro817Pro	synonymous	Exon 16 of 16	ENSP00000339611.4	O43526-4

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00245 AC: 569 AN: 232084 AF XY: 0.00257

Gnomad AFR exome AF: 0.000846

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00453 AC: 6592 AN: 1454096 Hom.: 16 Cov.: 30 AF XY: 0.00431 AC XY: 3119 AN XY: 723056

African (AFR) AF: 0.000599 AC: 20 AN: 33390

American (AMR) AF: 0.00143 AC: 63 AN: 44040

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25924

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39414

South Asian (SAS) AF: 0.00258 AC: 221 AN: 85638

European-Finnish (FIN) AF: 0.00586 AC: 295 AN: 50384

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.00515 AC: 5712 AN: 1109570

Other (OTH) AF: 0.00457 AC: 274 AN: 59974

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.00258 AC XY: 192 AN XY: 74510

African (AFR) AF: 0.00118 AC: 49 AN: 41594

American (AMR) AF: 0.00124 AC: 19 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00397 AC: 270 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00288 Hom.: 0

Bravo AF: 0.00226

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		-1.5
Mutation Taster		=97/3	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: rs147274045; hg19: chr20-62038072;