NM_000744.7:c.1352C>T

Variant names:

• chr20-63350059-G-A
• rs55915440
• NM_000744.7:c.1352C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000744.7(CHRNA4):​c.1352C>T​(p.Pro451Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,512,448 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P451R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.382
• Publications: 10 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005767554).
• BP6: Variant 20-63350059-G-A is Benign according to our data. Variant chr20-63350059-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 429 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.1352C>T	p.Pro451Leu	missense	Exon 5 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.824C>T	p.Pro275Leu	missense	Exon 5 of 6	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.1561C>T		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.1352C>T	p.Pro451Leu	missense	Exon 5 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.2000C>T		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.1422C>T		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152208 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00307 AC: 405 AN: 131754 AF XY: 0.00318

Gnomad AFR exome AF: 0.000224

Gnomad AMR exome AF: 0.000893

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.0000801

Gnomad FIN exome AF: 0.000668

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00372 AC: 5061 AN: 1360122 Hom.: 17 Cov.: 83 AF XY: 0.00388 AC XY: 2582 AN XY: 665314

African (AFR) AF: 0.000322 AC: 10 AN: 31064

American (AMR) AF: 0.00125 AC: 40 AN: 32008

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 396 AN: 21452

East Asian (EAS) AF: 0.0000539 AC: 2 AN: 37136

South Asian (SAS) AF: 0.00960 AC: 682 AN: 71022

European-Finnish (FIN) AF: 0.00104 AC: 47 AN: 45340

Middle Eastern (MID) AF: 0.00235 AC: 12 AN: 5102

European-Non Finnish (NFE) AF: 0.00342 AC: 3626 AN: 1060934

Other (OTH) AF: 0.00439 AC: 246 AN: 56064

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152326 Hom.: 3 Cov.: 33 AF XY: 0.00256 AC XY: 191 AN XY: 74482

African (AFR) AF: 0.000529 AC: 22 AN: 41584

American (AMR) AF: 0.00261 AC: 40 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00508 Hom.: 4

Bravo AF: 0.00261

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.00242 AC: 20

ExAC AF: 0.00270 AC: 316

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.51
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.38
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.14	T
Polyphen		0.0040	B
Vest4		0.15
MVP		0.74
MPC		0.41
ClinPred		0.0025	T
GERP RS		2.6
Varity_R		0.028
gMVP		0.27
Mutation Taster		=96/4	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: rs55915440; hg19: chr20-61981411; COSMIC: COSV105292768; COSMIC: COSV105292768;