Genetic Variant CHRNA4:p.Pro14Gln (chr20-63361125-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000744.7(CHRNA4):c.41C>A(p.Pro14Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000302 in 1,326,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

CHRNA4
NM_000744.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.673

Publications

0 publications found

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]

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

CHRNA4 links:

ENSG00000203900 (HGNC:):

ENSG00000203900 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14382565).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA4	NM_000744.7	MANE Select	c.41C>A	p.Pro14Gln	missense	Exon 1 of 6	NP_000735.1
CHRNA4	NR_046317.2		n.225C>A		non_coding_transcript_exon	Exon 1 of 6
CHRNA4	NM_001256573.2		c.-471+52C>A		intron	N/A	NP_001243502.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.41C>A	p.Pro14Gln	missense	Exon 1 of 6	ENSP00000359285.4
CHRNA4	ENST00000627000.1	TSL:1	n.41C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000486914.1
CHRNA4	ENST00000463705.5	TSL:1	n.1032-10098C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000302

AC:

AN:

1326120

Hom.:

Cov.:

AF XY:

0.00000459

AC XY:

AN XY:

653064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26912

American (AMR)

AF:

0.00

AC:

AN:

28650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23574

East Asian (EAS)

AF:

0.00

AC:

AN:

29808

South Asian (SAS)

AF:

0.00

AC:

AN:

73328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3984

European-Non Finnish (NFE)

AF:

0.00000380

AC:

AN:

1052362

Other (OTH)

AF:

0.00

AC:

AN:

55038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

4.8

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.12

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.26

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

PhyloP100

-0.67

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.13

REVEL

Benign

0.13

Sift

Benign

0.28

Sift4G

Benign

0.24

Polyphen

0.0010

Vest4

0.18

MutPred

0.34

Gain of helix (P = 0.005)

MVP

0.59

MPC

0.37

ClinPred

0.28

GERP RS

-3.3

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.077

gMVP

0.36

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over