chr8-132122131-C-T

Variant names:

• chr8-132122131-C-T
• rs75865310
• NM_004519.4:c.*7131G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004519.4(KCNQ3):​c.*7131G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 152,288 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (273 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.28
• 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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• self-limited familial neonatal epilepsy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-132122131-C-T is Benign according to our data. Variant chr8-132122131-C-T is described in ClinVar as Benign. ClinVar VariationId is 361760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.*7131G>A		3_prime_UTR	Exon 15 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.*7131G>A		3_prime_UTR	Exon 15 of 15	NP_001191753.1	O43525-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.*7131G>A		3_prime_UTR	Exon 15 of 15	ENSP00000373648.3	O43525-1

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 8001 AN: 152130 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0913

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0470

GnomAD4 exome AF: 0.100 AC: 4 AN: 40 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 4 AN XY: 32

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.105 AC: 4 AN: 38

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0526 AC: 8004 AN: 152248 Hom.: 273 Cov.: 32 AF XY: 0.0518 AC XY: 3855 AN XY: 74424

African (AFR) AF: 0.0173 AC: 720 AN: 41556

American (AMR) AF: 0.0352 AC: 539 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 208 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4822

European-Finnish (FIN) AF: 0.0913 AC: 969 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0786 AC: 5347 AN: 68006

Other (OTH) AF: 0.0465 AC: 98 AN: 2108

Alfa AF: 0.0594 Hom.: 31

Bravo AF: 0.0476

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Benign neonatal seizures (1)
-	-	1	not provided (1)
-	-	1	Seizures, benign familial neonatal, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.017
DANN	Benign	0.61
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs75865310; hg19: chr8-133134378;