chr20-63350095-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000744.7(CHRNA4):c.1316A>C(p.Lys439Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,529,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

CHRNA4
NM_000744.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.305

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12420726).

BP6

Variant 20-63350095-T-G is Benign according to our data. Variant chr20-63350095-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205026.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNA4	NM_000744.7 link	c.1316A>C	p.Lys439Thr	missense_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 link	c.788A>C	p.Lys263Thr	missense_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2 link	n.1525A>C		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 link	c.1316A>C	p.Lys439Thr	missense_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.00000726

AC:

AN:

1377912

Hom.:

Cov.:

AF XY:

0.00000444

AC XY:

AN XY:

675374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31754

American (AMR)

AF:

0.000170

AC:

AN:

35370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22296

East Asian (EAS)

AF:

0.00

AC:

AN:

37372

South Asian (SAS)

AF:

0.00

AC:

AN:

73788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068160

Other (OTH)

AF:

0.0000528

AC:

AN:

56814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

AF:

0.0000789

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41408

American (AMR)

AF:

0.000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 14, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This amino acid substitution is not predicted to occur within the transmembrane region of the protein, where the vast majority of pathogenic missense variants have been identified in association with epilepsy (Steinlein et al., 2010)

Mar 01, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Jul 24, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K439T variant (also known as c.1316A>C), located in coding exon 5 of the CHRNA4 gene, results from an A to C substitution at nucleotide position 1316. The lysine at codon 439 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to

Uncertain:1

Apr 14, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.0

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.75

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.7

L;.

PhyloP100

0.30

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.90

N;.

REVEL

Benign

0.18

Sift

Benign

0.24

T;.

Sift4G

Benign

0.41

T;T

Vest4

0.19

ClinPred

0.30

GERP RS

1.5

Varity_R

0.10

gMVP

0.27

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over