20-63350538-G-GAGC

Variant names:

• chr20-63350538-G-GAGC
• rs281865067
• NM_000744.7:c.870_872dupGCT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP3 PP5

The NM_000744.7(CHRNA4):​c.870_872dupGCT​(p.Leu291dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L291L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA4 NM_000744.7 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.03
• Publications: 4 publications found

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA4 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000744.7. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 20-63350538-G-GAGC is Pathogenic according to our data. Variant chr20-63350538-G-GAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 41030.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. 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
	CHRNA4	NM_000744.7	MANE Select	c.870_872dupGCT	p.Leu291dup	disruptive_inframe_insertion	Exon 5 of 6	NP_000735.1
	CHRNA4	NM_001256573.2		c.342_344dupGCT	p.Leu115dup	disruptive_inframe_insertion	Exon 5 of 6	NP_001243502.1
	CHRNA4	NR_046317.2		n.1079_1081dupGCT		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.870_872dupGCT	p.Leu291dup	disruptive_inframe_insertion	Exon 5 of 6	ENSP00000359285.4
	CHRNA4	ENST00000463705.5	TSL:1	n.1518_1520dupGCT		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.940_942dupGCT		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 99

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1 Pathogenic:1 Other:1

Sep 10, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs281865067; hg19: chr20-61981890;