chr20-63361113-A-AGCAGCAGCAGCGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_000744.7(CHRNA4):c.38_52dupCGCCGCTGCTGCTGC(p.Pro13_Leu17dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,476,870 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

CHRNA4
NM_000744.7 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.07

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000744.7

BP6

Variant 20-63361113-A-AGCAGCAGCAGCGGCG is Benign according to our data. Variant chr20-63361113-A-AGCAGCAGCAGCGGCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447035.

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7 link	c.38_52dupCGCCGCTGCTGCTGC	p.Pro13_Leu17dup	conservative_inframe_insertion	Exon 1 of 6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NR_046317.2 link	n.222_236dupCGCCGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 6
CHRNA4	NM_001256573.2 link	c.-471+49_-471+63dupCGCCGCTGCTGCTGC		intron_variant	Intron 1 of 5		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
LOC100130587	NR_110634.1 link	n.183-696_183-682dupAGCGGCGGCAGCAGC		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 link	c.38_52dupCGCCGCTGCTGCTGC	p.Pro13_Leu17dup	conservative_inframe_insertion	Exon 1 of 6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

84992

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1325076

Hom.:

Cov.:

AF XY:

0.0000215

AC XY:

AN XY:

652624

show subpopulations

African (AFR)

AF:

0.0000372

AC:

AN:

26884

American (AMR)

AF:

0.00

AC:

AN:

28368

Ashkenazi Jewish (ASJ)

AF:

0.0000425

AC:

AN:

23512

East Asian (EAS)

AF:

0.00

AC:

AN:

29794

South Asian (SAS)

AF:

0.0000820

AC:

AN:

73196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3980

European-Non Finnish (NFE)

AF:

0.0000133

AC:

AN:

1051898

Other (OTH)

AF:

0.0000363

AC:

AN:

55022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.0000198

AC:

AN:

151794

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41366

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame duplication of 5 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Jan 19, 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

PhyloP100

1.1

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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