rs1554622834

Variant names:

• chr8-132140095-C-T
• rs1554622834
• NM_004519.4:c.1549G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004519.4(KCNQ3):​c.1549G>A​(p.Ala517Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A517A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.605
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15011355).
• BP6: Variant 8-132140095-C-T is Benign according to our data. Variant chr8-132140095-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 538558.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.1549G>A	p.Ala517Thr	missense_variant	Exon 11 of 15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.1549G>A	p.Ala517Thr	missense_variant	Exon 11 of 15	1	NM_004519.4	ENSP00000373648.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Benign neonatal seizures Benign:1

Jul 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.63
DEOGEN2	Uncertain	0.55	D;.;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	-0.19	N;.;.;.;.
PhyloP100		0.60
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.4	N;.;N;N;.
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;.;T;T;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0	B;.;.;B;.
Vest4		0.29
MutPred		0.44		Gain of phosphorylation at A517 (P = 0.099);.;.;Gain of phosphorylation at A517 (P = 0.099);.;
MVP		0.47
MPC		0.90
ClinPred		0.21	T
GERP RS		4.1
Varity_R		0.037
gMVP		0.34
Mutation Taster		=54/46	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: rs1554622834; hg19: chr8-133152342; COSMIC: COSV66480979;