8-132186181-C-G

Variant names:

• chr8-132186181-C-G
• rs1060500604
• NM_004519.4:c.387G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP6_Moderate BP7

The NM_004519.4(KCNQ3):​c.387G>C​(p.Val129Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ3 NM_004519.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.4363
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.39
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 8-132186181-C-G is Benign according to our data. Variant chr8-132186181-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 405214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.387G>C	p.Val129Val	splice_region synonymous	Exon 2 of 15	NP_004510.1
	KCNQ3	NM_001204824.2		c.27G>C	p.Met9Ile	missense splice_region	Exon 2 of 15	NP_001191753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.387G>C	p.Val129Val	splice_region synonymous	Exon 2 of 15	ENSP00000373648.3
	KCNQ3	ENST00000521134.6	TSL:2	c.27G>C	p.Met9Ile	missense splice_region	Exon 2 of 15	ENSP00000429799.1
	KCNQ3	ENST00000638588.1	TSL:5	c.60G>C	p.Arg20Ser	missense splice_region	Exon 2 of 15	ENSP00000491940.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Benign neonatal seizures Benign:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.28	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	0.87	D
PhyloP100		2.4
PROVEAN	Benign	1.6	N
REVEL	Uncertain	0.46
Sift	Benign	0.093	T
Sift4G	Benign	0.12	T
Vest4		0.21
MutPred		0.48		Loss of disorder (P = 0.1037)
MVP		0.74
ClinPred		0.35	T
GERP RS		3.9
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.55
SpliceAI score (max)		0.040		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: rs1060500604; hg19: chr8-133198428;