20-63350253-G-C

Variant names:

• chr20-63350253-G-C
• rs45564639
• NM_000744.7:c.1158C>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.1158C>G​(p.Pro386Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,609,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P386P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.44
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-63350253-G-C is Benign according to our data. Variant chr20-63350253-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.44 with no splicing effect.
• BS2: High AC in GnomAd4 at 123 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.1158C>G	p.Pro386Pro	synonymous	Exon 5 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.630C>G	p.Pro210Pro	synonymous	Exon 5 of 6	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.1367C>G		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.1158C>G	p.Pro386Pro	synonymous	Exon 5 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.1806C>G		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.1228C>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000185 AC: 44 AN: 238310 AF XY: 0.000146

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1457442 Hom.: 0 Cov.: 99 AF XY: 0.000109 AC XY: 79 AN XY: 724816

African (AFR) AF: 0.00275 AC: 92 AN: 33432

American (AMR) AF: 0.000406 AC: 18 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51562

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1110662

Other (OTH) AF: 0.000249 AC: 15 AN: 60144

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74466

African (AFR) AF: 0.00267 AC: 111 AN: 41564

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000786

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	CHRNA4-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.017
DANN	Benign	0.46
PhyloP100		-6.4
Mutation Taster		=100/0	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: rs45564639; hg19: chr20-61981605;