Genetic Variant CHRNA7:c.196-8_196-5dupTTTT (chr15-32101283-C-CTTTT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000746.6(CHRNA7):c.196-8_196-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,451,178 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00069 ( 3 hom. )

Consequence

CHRNA7
NM_000746.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.508

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 33 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	Effect	Exon Rank	Protein	UniProt
CHRNA7	NM_000746.6	MANE Select	c.196-8_196-5dupTTTT	splice_region intron	N/A	NP_000737.1	P36544-1
CHRNA7	NM_001190455.3		c.283-8_283-5dupTTTT	splice_region intron	N/A	NP_001177384.1	P36544-2
CHRNA7	NR_046324.1		n.308-8_308-5dupTTTT	splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.196-8_196-5dupTTTT	splice_region intron	N/A	ENSP00000303727.2	P36544-1
CHRNA7	ENST00000635759.1	TSL:1	n.61-8_61-5dupTTTT	splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
CHRNA7	ENST00000637786.2	TSL:1	n.196-8_196-5dupTTTT	splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes

AF:

0.000233

AC:

AN:

141330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000470

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000205

Gnomad SAS

AF:

0.00157

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000107

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00202

AC:

298

AN:

147816

AF XY:

0.00206

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.00384

Gnomad FIN exome

AF:

0.00161

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.000688

AC:

901

AN:

1309846

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

474

AN XY:

652858

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00140

AC:

AN:

28510

American (AMR)

AF:

0.00146

AC:

AN:

29354

Ashkenazi Jewish (ASJ)

AF:

0.000307

AC:

AN:

22778

East Asian (EAS)

AF:

0.00134

AC:

AN:

36624

South Asian (SAS)

AF:

0.00144

AC:

104

AN:

72350

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

47452

Middle Eastern (MID)

AF:

0.000198

AC:

AN:

5048

European-Non Finnish (NFE)

AF:

0.000566

AC:

574

AN:

1013474

Other (OTH)

AF:

0.000608

AC:

AN:

54256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.321

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000233

AC:

AN:

141332

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

AN XY:

68054

show subpopulations

African (AFR)

AF:

0.000469

AC:

AN:

38358

American (AMR)

AF:

0.00

AC:

AN:

14238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.000206

AC:

AN:

4856

South Asian (SAS)

AF:

0.00158

AC:

AN:

4424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

65574

Other (OTH)

AF:

0.00

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.51

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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15-32101283-CTTTTTTT-CTTTTTTTTTTT

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