NM_172107.4:c.*5962G>T

Variant names:

• chr20-63400682-C-A
• rs3746372
• NM_172107.4:c.*5962G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_172107.4(KCNQ2):​c.*5962G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 398,554 control chromosomes in the GnomAD database, including 11,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3529 hom., cov: 33)
  • Exomes 𝑓: 0.24 (8007 hom.)
• Consequence: KCNQ2 NM_172107.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.511
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012863576).
• BP6: Variant 20-63400682-C-A is Benign according to our data. Variant chr20-63400682-C-A is described in ClinVar as Benign. ClinVar VariationId is 3255266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.*5962G>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.*5962G>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28752 AN: 152128 Hom.: 3519 Cov.: 33

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.195

GnomAD4 exome AF: 0.243 AC: 59776 AN: 246310 Hom.: 8007 Cov.: 0 AF XY: 0.243 AC XY: 30286 AN XY: 124834

African (AFR) AF: 0.0439 AC: 315 AN: 7180

American (AMR) AF: 0.299 AC: 2219 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 2427 AN: 9232

East Asian (EAS) AF: 0.424 AC: 9708 AN: 22892

South Asian (SAS) AF: 0.332 AC: 1008 AN: 3040

European-Finnish (FIN) AF: 0.275 AC: 5724 AN: 20836

Middle Eastern (MID) AF: 0.221 AC: 286 AN: 1294

European-Non Finnish (NFE) AF: 0.217 AC: 34272 AN: 158034

Other (OTH) AF: 0.233 AC: 3817 AN: 16370

GnomAD4 genome AF: 0.189 AC: 28770 AN: 152244 Hom.: 3529 Cov.: 33 AF XY: 0.196 AC XY: 14575 AN XY: 74442

African (AFR) AF: 0.0449 AC: 1866 AN: 41578

American (AMR) AF: 0.259 AC: 3959 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 875 AN: 3470

East Asian (EAS) AF: 0.429 AC: 2216 AN: 5168

South Asian (SAS) AF: 0.323 AC: 1560 AN: 4828

European-Finnish (FIN) AF: 0.280 AC: 2970 AN: 10606

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.216 AC: 14664 AN: 67992

Other (OTH) AF: 0.202 AC: 427 AN: 2110

Alfa AF: 0.209 Hom.: 4759

Bravo AF: 0.182

TwinsUK AF: 0.186 AC: 688

ALSPAC AF: 0.194 AC: 747

Asia WGS AF: 0.373 AC: 1295 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 57% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 53. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.83
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0013	T
PhyloP100		0.51
Vest4		0.11
MVP		0.36
GERP RS		3.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3746372; hg19: chr20-62032035;