rs1555870554

chr20-63439696-T-Achr20-63439696-T-G

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):c.829A>T(p.Thr277Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T277A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PS1: Transcript NM_172107.4 (KCNQ2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2074244
• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63439696-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2500737.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 20-63439696-T-A is Pathogenic according to our data. Variant chr20-63439696-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.829A>T	p.Thr277Ser	missense_variant	6/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.829A>T	p.Thr277Ser	missense_variant	6/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

- -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Jan 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.17	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.032	D
MVP		0.78
ClinPred		1.0	D
GERP RS		4.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555870554; hg19: chr20-62071049;