NM_000746.6:c.3G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The NM_000746.6(CHRNA7):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,551,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CHRNA7
NM_000746.6 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

CHRNA7 (HGNC:1960): (cholinergic receptor nicotinic alpha 7 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA7 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
epilepsy
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

CHRNA7 links:

LOC124903441 (HGNC:):

LOC124903441 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 63 codons. Genomic position: 32031029. Lost 0.124 part of the original CDS.

BS2

High AC in GnomAdExome4 at 16 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000746.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA7	NM_000746.6	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	NP_000737.1	P36544-1
CHRNA7	NM_001190455.3		c.3G>A	p.Met1?	start_lost	Exon 1 of 10	NP_001177384.1	P36544-2
CHRNA7	NR_046324.1		n.115G>A		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000303727.2	P36544-1
CHRNA7	ENST00000637786.2	TSL:1	n.3G>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000490015.1	A0A1B0GU93
CHRNA7	ENST00000454250.7	TSL:2	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000407546.3	P36544-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000129

AC:

AN:

155254

AF XY:

0.0000230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

0.0000114

AC:

AN:

1399786

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

693628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29280

American (AMR)

AF:

0.00

AC:

AN:

39562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24786

East Asian (EAS)

AF:

0.00

AC:

AN:

34884

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4658

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

1088432

Other (OTH)

AF:

0.00

AC:

AN:

58052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000173

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.42

PhyloP100

1.3

PROVEAN

Benign

-0.17

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

0.0010

Vest4

0.86

MutPred

0.98

Loss of methylation at R2 (P = 0.0648)

MVP

0.81

ClinPred

0.97

GERP RS

3.6

PromoterAI

0.073

Neutral

(source)

Varity_R

0.88

gMVP

0.51

Mutation Taster

=18/182

disease causing

(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