dbSNP rs199879109: CHRNA4:c.*144G>C (chr20-63346594-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000744.7(CHRNA4):c.*144G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,197,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CHRNA4
NM_000744.7 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.17

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 20-63346594-C-G is Benign according to our data. Variant chr20-63346594-C-G is described in ClinVar as Benign. ClinVar VariationId is 1234517.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 129 AD gene.

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	Effect	Exon Rank	Protein	UniProt
CHRNA4	NM_000744.7	MANE Select	c.*144G>C	3_prime_UTR	Exon 6 of 6	NP_000735.1	P43681-1
CHRNA4	NM_001256573.2		c.*144G>C	3_prime_UTR	Exon 6 of 6	NP_001243502.1	Q4VAQ3
CHRNA4	NR_046317.2		n.2237G>C	non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.*144G>C	3_prime_UTR	Exon 6 of 6	ENSP00000359285.4	P43681-1
CHRNA4	ENST00000463705.5	TSL:1	n.2676G>C	non_coding_transcript_exon	Exon 5 of 5
CHRNA4	ENST00000467563.3	TSL:1	n.2098G>C	splice_region non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.000834

AC:

127

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000245

AC:

AN:

134626

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.00371

Gnomad AMR exome

AF:

0.000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

110

AN:

1044898

Hom.:

Cov.:

AF XY:

0.0000924

AC XY:

AN XY:

530060

show subpopulations

African (AFR)

AF:

0.00305

AC:

AN:

24906

American (AMR)

AF:

0.000313

AC:

AN:

35168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23012

East Asian (EAS)

AF:

0.00

AC:

AN:

34076

South Asian (SAS)

AF:

0.0000278

AC:

AN:

71912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3438

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

772570

Other (OTH)

AF:

0.000237

AC:

AN:

46476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000847

AC:

129

AN:

152376

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00284

AC:

118

AN:

41586

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68046

Other (OTH)

AF:

0.00189

AC:

AN:

2116

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:

0.000216

Hom.:

Bravo

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.6

(source)

DANN

Benign

0.57

PhyloP100

-1.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over