rs55915440

chr20-63350059-G-Achr20-63350059-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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. 15/20 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:9
• Conservation: PhyloP100: 0.382

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 Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 136759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63350059-G-A is described in Lovd as [Likely_benign]. Variant chr20-63350059-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00282 (429/152326) while in subpopulation SAS AF= 0.00828 (40/4828). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1352C>T	p.Pro451Leu	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.824C>T	p.Pro275Leu	missense_variant	5/6
CHRNA4	NR_046317.2	n.1561C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1352C>T	p.Pro451Leu	missense_variant	5/6	1	NM_000744.7	P1

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

GnomAD3 exomes AF: 0.00307 AC: 405 AN: 131754 Hom.: 1 AF XY: 0.00318 AC XY: 221 AN XY: 69600

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 SAS exome AF: 0.00891

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

Gnomad4 AFR exome AF: 0.000322

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0185

Gnomad4 EAS exome AF: 0.0000539

Gnomad4 SAS exome AF: 0.00960

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00439

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

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00662

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

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CHRNA4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.14
Sift	Benign	0.21	T;.
Sift4G	Benign	0.14	T;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

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: rs55915440; hg19: chr20-61981411; COSMIC: COSV105292768; COSMIC: COSV105292768;