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rs1044396

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000744.7(CHRNA4):c.1629C>T(p.Ser543=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,609,060 control chromosomes in the GnomAD database, including 220,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 15024 hom., cov: 34)
Exomes 𝑓: 0.52 ( 205217 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.929
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 20-63349782-G-A is Benign according to our data. Variant chr20-63349782-G-A is described in ClinVar as [Benign]. Clinvar id is 93427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.929 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHRNA4NM_000744.7 linkuse as main transcriptc.1629C>T p.Ser543= synonymous_variant 5/6 ENST00000370263.9
CHRNA4NM_001256573.2 linkuse as main transcriptc.1101C>T p.Ser367= synonymous_variant 5/6
CHRNA4NR_046317.2 linkuse as main transcriptn.1838C>T non_coding_transcript_exon_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHRNA4ENST00000370263.9 linkuse as main transcriptc.1629C>T p.Ser543= synonymous_variant 5/61 NM_000744.7 P1P43681-1

Frequencies

GnomAD3 genomes
AF:
0.404
AC:
61427
AN:
152032
Hom.:
15016
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.128
Gnomad AMI
AF:
0.379
Gnomad AMR
AF:
0.498
Gnomad ASJ
AF:
0.432
Gnomad EAS
AF:
0.253
Gnomad SAS
AF:
0.424
Gnomad FIN
AF:
0.524
Gnomad MID
AF:
0.396
Gnomad NFE
AF:
0.541
Gnomad OTH
AF:
0.413
GnomAD3 exomes
AF:
0.471
AC:
116275
AN:
247118
Hom.:
29237
AF XY:
0.475
AC XY:
63808
AN XY:
134266
show subpopulations
Gnomad AFR exome
AF:
0.118
Gnomad AMR exome
AF:
0.528
Gnomad ASJ exome
AF:
0.431
Gnomad EAS exome
AF:
0.257
Gnomad SAS exome
AF:
0.436
Gnomad FIN exome
AF:
0.530
Gnomad NFE exome
AF:
0.539
Gnomad OTH exome
AF:
0.486
GnomAD4 exome
AF:
0.523
AC:
761794
AN:
1456910
Hom.:
205217
Cov.:
77
AF XY:
0.521
AC XY:
376959
AN XY:
724028
show subpopulations
Gnomad4 AFR exome
AF:
0.108
Gnomad4 AMR exome
AF:
0.526
Gnomad4 ASJ exome
AF:
0.424
Gnomad4 EAS exome
AF:
0.272
Gnomad4 SAS exome
AF:
0.438
Gnomad4 FIN exome
AF:
0.529
Gnomad4 NFE exome
AF:
0.555
Gnomad4 OTH exome
AF:
0.488
GnomAD4 genome
AF:
0.404
AC:
61447
AN:
152150
Hom.:
15024
Cov.:
34
AF XY:
0.408
AC XY:
30309
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.128
Gnomad4 AMR
AF:
0.498
Gnomad4 ASJ
AF:
0.432
Gnomad4 EAS
AF:
0.253
Gnomad4 SAS
AF:
0.426
Gnomad4 FIN
AF:
0.524
Gnomad4 NFE
AF:
0.541
Gnomad4 OTH
AF:
0.416
Alfa
AF:
0.500
Hom.:
19738
Bravo
AF:
0.388
Asia WGS
AF:
0.348
AC:
1212
AN:
3478
EpiCase
AF:
0.527
EpiControl
AF:
0.521

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 12, 2016- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 28877969) -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncApr 28, 2017- -
Autosomal dominant nocturnal frontal lobe epilepsy 1 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 08, 2016This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Nicotine addiction, protection against Benign:1
protective, no assertion criteria providedliterature onlyOMIMJul 01, 2004- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
Cadd
Benign
0.51
Dann
Benign
0.61

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1044396; hg19: chr20-61981134; COSMIC: COSV64718823; COSMIC: COSV64718823; API