rs2273500

Variant names:

• chr20-63355597-T-C
• rs2273500
• NM_000744.7:c.383+378A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000744.7(CHRNA4):​c.383+378A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,305,208 control chromosomes in the GnomAD database, including 17,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2035 hom., cov: 32)
  • Exomes 𝑓: 0.16 (15129 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Scores: Splicing: ADA: 0.00006553
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.67
• Publications: 33 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.955197).
• BP6: Variant 20-63355597-T-C is Benign according to our data. Variant chr20-63355597-T-C is described in ClinVar as Benign. ClinVar VariationId is 3255299.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.295 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.383+378A>G		intron	N/A	NP_000735.1
	CHRNA4	NM_001256573.2		c.-146+360A>G		intron	N/A	NP_001243502.1
	CHRNA4	NR_046317.2		n.592+378A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.383+378A>G		intron	N/A	ENSP00000359285.4
	CHRNA4	ENST00000463705.5	TSL:1	n.1032-4570A>G		intron	N/A
	CHRNA4	ENST00000467563.3	TSL:1	n.453+360A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24284 AN: 152010 Hom.: 2032 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.164 AC: 22355 AN: 136100 AF XY: 0.175

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0818

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.156 AC: 179348 AN: 1153080 Hom.: 15129 Cov.: 30 AF XY: 0.160 AC XY: 90597 AN XY: 565876

African (AFR) AF: 0.159 AC: 3979 AN: 25036

American (AMR) AF: 0.0835 AC: 2395 AN: 28686

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 3109 AN: 16726

East Asian (EAS) AF: 0.130 AC: 1852 AN: 14296

South Asian (SAS) AF: 0.285 AC: 21749 AN: 76302

European-Finnish (FIN) AF: 0.216 AC: 2946 AN: 13616

Middle Eastern (MID) AF: 0.214 AC: 960 AN: 4488

European-Non Finnish (NFE) AF: 0.145 AC: 135398 AN: 931248

Other (OTH) AF: 0.163 AC: 6960 AN: 42682

GnomAD4 genome AF: 0.160 AC: 24312 AN: 152128 Hom.: 2035 Cov.: 32 AF XY: 0.164 AC XY: 12190 AN XY: 74382

African (AFR) AF: 0.153 AC: 6359 AN: 41494

American (AMR) AF: 0.126 AC: 1931 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 610 AN: 3468

East Asian (EAS) AF: 0.136 AC: 702 AN: 5164

South Asian (SAS) AF: 0.308 AC: 1486 AN: 4822

European-Finnish (FIN) AF: 0.226 AC: 2394 AN: 10596

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.152 AC: 10311 AN: 67966

Other (OTH) AF: 0.162 AC: 343 AN: 2114

Alfa AF: 0.148 Hom.: 2770

Bravo AF: 0.147

TwinsUK AF: 0.141 AC: 522

ALSPAC AF: 0.144 AC: 556

ExAC AF: 0.163 AC: 3506

Asia WGS AF: 0.214 AC: 746 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.96	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.2
DANN	Benign	0.49
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00039	N
PhyloP100		-6.7
GERP RS		-0.045
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs2273500; hg19: chr20-61986949; COSMIC: COSV64718268; COSMIC: COSV64718268;