rs140674819

Variant names:

• chr20-63406734-G-A
• rs140674819
• NM_172107.4:c.2529C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63406734-G-A
• chr20-63406734-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172107.4(KCNQ2):​c.2529C>T​(p.Ser843Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000635 in 1,610,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.473
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 20-63406734-G-A is Benign according to our data. Variant chr20-63406734-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00044 (67/152350) while in subpopulation NFE AF = 0.000794 (54/68032). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 67 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.2529C>T	p.Ser843Ser	synonymous	Exon 17 of 17	NP_742105.1	O43526-1
	KCNQ2	NM_001382235.1		c.2583C>T	p.Ser861Ser	synonymous	Exon 17 of 17	NP_001369164.1	A0A9L9PXL0
	KCNQ2	NM_172106.3		c.2475C>T	p.Ser825Ser	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.2529C>T	p.Ser843Ser	synonymous	Exon 17 of 17	ENSP00000352035.2	O43526-1
	KCNQ2	ENST00000626839.2	TSL:1	c.2475C>T	p.Ser825Ser	synonymous	Exon 16 of 16	ENSP00000486706.1	O43526-2
	KCNQ2	ENST00000344462.8	TSL:1	c.2436C>T	p.Ser812Ser	synonymous	Exon 16 of 16	ENSP00000339611.4	O43526-4

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000460 AC: 111 AN: 241368 AF XY: 0.000546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000493

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000655 AC: 955 AN: 1457700 Hom.: 0 Cov.: 30 AF XY: 0.000684 AC XY: 496 AN XY: 725036

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.000225 AC: 10 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.000826 AC: 71 AN: 85918

European-Finnish (FIN) AF: 0.000546 AC: 28 AN: 51328

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000729 AC: 810 AN: 1110994

Other (OTH) AF: 0.000532 AC: 32 AN: 60196

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152350 Hom.: 0 Cov.: 34 AF XY: 0.000497 AC XY: 37 AN XY: 74502

African (AFR) AF: 0.000144 AC: 6 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000665 Hom.: 1

Bravo AF: 0.000385

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
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	-0.58
CADD	Benign	3.8
DANN	Benign	0.72
PhyloP100		-0.47
Mutation Taster		=89/11	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: rs140674819; hg19: chr20-62038087; COSMIC: COSV60540720; COSMIC: COSV60540720;