rs748440038

Variant names:

• chr20-63359583-G-A
• rs748440038
• NM_000744.7:c.193C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63359583-G-A
• chr20-63359583-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001256573.2(CHRNA4):​c.-354C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CHRNA4 NM_001256573.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.193C>T	p.Arg65Cys	missense_variant	Exon 2 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-354C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6		NP_001243502.1
CHRNA4	NM_001256573.2	c.-354C>T		5_prime_UTR_variant	Exon 2 of 6		NP_001243502.1
CHRNA4	NR_046317.2	n.377C>T		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.193C>T	p.Arg65Cys	missense_variant	Exon 2 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 249850 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460360 Hom.: 0 Cov.: 38 AF XY: 0.0000124 AC XY: 9 AN XY: 726470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ExAC AF: 0.00000829 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 65 of the CHRNA4 protein (p.Arg65Cys). This variant is present in population databases (rs748440038, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 543520). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNA4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.094
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.45
Sift	Benign	0.28	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.72	P
Vest4		0.65
MutPred		0.42		Loss of MoRF binding (P = 0.0325);
MVP		0.88
MPC		1.4
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.14
gMVP		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

Other links and lift over

dbSNP: rs748440038; hg19: chr20-61990935; COSMIC: COSV64717950; COSMIC: COSV64717950;