rs2273505

Variant names:

• chr20-63359526-C-T
• rs2273505
• NM_000744.7:c.228+22G>A

Variant summary

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

The NM_000744.7(CHRNA4):​c.228+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,612,242 control chromosomes in the GnomAD database, including 5,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (744 hom., cov: 34)
  • Exomes 𝑓: 0.077 (5140 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.30
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 20-63359526-C-T is Benign according to our data. Variant chr20-63359526-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

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.228+22G>A		intron	N/A	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.-319+22G>A		intron	N/A	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.412+22G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.228+22G>A		intron	N/A	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.1032-8499G>A		intron	N/A
	CHRNA4	ENST00000467563.3	TSL:1	n.280+22G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0955 AC: 14534 AN: 152138 Hom.: 743 Cov.: 34

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0918 AC: 22896 AN: 249412 AF XY: 0.0948

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0479

Gnomad ASJ exome AF: 0.0964

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.0886

Gnomad NFE exome AF: 0.0746

Gnomad OTH exome AF: 0.0909

GnomAD4 exome AF: 0.0774 AC: 112965 AN: 1459986 Hom.: 5140 Cov.: 38 AF XY: 0.0797 AC XY: 57902 AN XY: 726300

African (AFR) AF: 0.141 AC: 4717 AN: 33468

American (AMR) AF: 0.0512 AC: 2288 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2638 AN: 26120

East Asian (EAS) AF: 0.119 AC: 4710 AN: 39684

South Asian (SAS) AF: 0.159 AC: 13738 AN: 86246

European-Finnish (FIN) AF: 0.0869 AC: 4514 AN: 51958

Middle Eastern (MID) AF: 0.167 AC: 958 AN: 5752

European-Non Finnish (NFE) AF: 0.0668 AC: 74302 AN: 1111704

Other (OTH) AF: 0.0845 AC: 5100 AN: 60340

GnomAD4 genome AF: 0.0956 AC: 14556 AN: 152256 Hom.: 744 Cov.: 34 AF XY: 0.0965 AC XY: 7183 AN XY: 74442

African (AFR) AF: 0.133 AC: 5522 AN: 41534

American (AMR) AF: 0.0765 AC: 1171 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3470

East Asian (EAS) AF: 0.125 AC: 648 AN: 5182

South Asian (SAS) AF: 0.162 AC: 783 AN: 4820

European-Finnish (FIN) AF: 0.0870 AC: 923 AN: 10608

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0713 AC: 4852 AN: 68024

Other (OTH) AF: 0.103 AC: 218 AN: 2110

Alfa AF: 0.0836 Hom.: 121

Bravo AF: 0.0941

Asia WGS AF: 0.143 AC: 496 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.18
DANN	Benign	0.70
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2273505; hg19: chr20-61990878;