rs80075498

Variant names:

• chr20-63361157-T-C
• rs80075498
• NM_000744.7:c.9A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-63361157-T-C
• chr20-63361157-T-A
• chr20-63361157-T-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000744.7(CHRNA4):​c.9A>G​(p.Leu3Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,479,910 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (11 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.645
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000203900 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 20-63361157-T-C is Benign according to our data. Variant chr20-63361157-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.645 with no splicing effect.
• BS2: High AC in GnomAd4 at 403 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.9A>G	p.Leu3Leu	synonymous	Exon 1 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.-471+20A>G		intron	N/A	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.193A>G		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.9A>G	p.Leu3Leu	synonymous	Exon 1 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000627000.1	TSL:1	n.9A>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000486914.1	A0A0D9SFU6
	CHRNA4	ENST00000463705.5	TSL:1	n.1032-10130A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 404 AN: 151226 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0226

Gnomad EAS AF: 0.000401

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.000476

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.00578

GnomAD2 exomes AF: 0.00417 AC: 356 AN: 85474 AF XY: 0.00454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000806

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00433

GnomAD4 exome AF: 0.00368 AC: 4884 AN: 1328574 Hom.: 11 Cov.: 30 AF XY: 0.00379 AC XY: 2483 AN XY: 654314

African (AFR) AF: 0.000223 AC: 6 AN: 26924

American (AMR) AF: 0.00125 AC: 36 AN: 28834

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 432 AN: 23568

East Asian (EAS) AF: 0.00 AC: 0 AN: 29854

South Asian (SAS) AF: 0.00666 AC: 491 AN: 73708

European-Finnish (FIN) AF: 0.00116 AC: 38 AN: 32738

Middle Eastern (MID) AF: 0.00328 AC: 13 AN: 3968

European-Non Finnish (NFE) AF: 0.00344 AC: 3625 AN: 1053852

Other (OTH) AF: 0.00441 AC: 243 AN: 55128

GnomAD4 genome AF: 0.00266 AC: 403 AN: 151336 Hom.: 2 Cov.: 31 AF XY: 0.00237 AC XY: 175 AN XY: 73942

African (AFR) AF: 0.000484 AC: 20 AN: 41336

American (AMR) AF: 0.00262 AC: 40 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 78 AN: 3458

East Asian (EAS) AF: 0.000403 AC: 2 AN: 4966

South Asian (SAS) AF: 0.00479 AC: 23 AN: 4800

European-Finnish (FIN) AF: 0.000476 AC: 5 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00329 AC: 223 AN: 67692

Other (OTH) AF: 0.00572 AC: 12 AN: 2098

Alfa AF: 0.00502 Hom.: 1

Bravo AF: 0.00253

Asia WGS AF: 0.00174 AC: 6 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		-0.65
PromoterAI		-0.0045	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs80075498; hg19: chr20-61992509; COSMIC: COSV64717905; COSMIC: COSV64717905;