rs199783192

Variant names:

• chr20-63349827-C-T
• rs199783192
• NM_000744.7:c.1584G>A

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.1584G>A​(p.Pro528Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,599,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.23
• Publications: 0 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=-0.86).
• BP6: Variant 20-63349827-C-T is Benign according to our data. Variant chr20-63349827-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.23 with no splicing effect.
• BS2: High AC in GnomAd4 at 30 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.1584G>A	p.Pro528Pro	synonymous	Exon 5 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.1056G>A	p.Pro352Pro	synonymous	Exon 5 of 6	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.1793G>A		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.1584G>A	p.Pro528Pro	synonymous	Exon 5 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.2232G>A		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.1654G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000248 AC: 60 AN: 242114 AF XY: 0.000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000312 AC: 451 AN: 1447008 Hom.: 1 Cov.: 82 AF XY: 0.000298 AC XY: 214 AN XY: 717098

African (AFR) AF: 0.0000603 AC: 2 AN: 33146

American (AMR) AF: 0.000317 AC: 14 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25726

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85520

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000379 AC: 418 AN: 1101912

Other (OTH) AF: 0.000252 AC: 15 AN: 59606

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74458

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000144

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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	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	-0.86
CADD	Benign	0.12
DANN	Benign	0.60
PhyloP100		-3.2
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: rs199783192; hg19: chr20-61981179;