rs2229957

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000079.4(CHRNA1):c.960C>T(p.His320His) variant causes a synonymous change. The variant allele was found at a frequency of 0.0732 in 1,613,996 control chromosomes in the GnomAD database, including 5,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 827 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4971 hom. )

Consequence

CHRNA1
NM_000079.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.79

Publications

16 publications found

Variant links:

Genes affected

CHRNA1 (HGNC:1955): (cholinergic receptor nicotinic alpha 1 subunit) The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]

CHRNA1 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 1A
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
lethal multiple pterygium syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myasthenic syndrome, congenital, 1B, fast-channel
Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHRNA1 links:

ENSG00000236449 (HGNC:):

ENSG00000236449 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-174749988-G-A is Benign according to our data. Variant chr2-174749988-G-A is described in ClinVar as Benign. ClinVar VariationId is 128735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4 link	c.960C>T	p.His320His	synonymous_variant	Exon 7 of 9	ENST00000348749.9	NP_000070.1	P02708-2Q53SH4
CHRNA1	NM_001039523.3 link	c.1035C>T	p.His345His	synonymous_variant	Exon 8 of 10		NP_001034612.1	P02708-1Q53SH4
CHRNA1	XM_017003256.2 link	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 9		XP_016858745.1
CHRNA1	XM_017003257.2 link	c.981C>T	p.His327His	synonymous_variant	Exon 6 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9 link	c.960C>T	p.His320His	synonymous_variant	Exon 7 of 9	1	NM_000079.4	ENSP00000261008.5		P02708-2

Frequencies

GnomAD3 genomes

AF:

0.0914

AC:

13892

AN:

152038

Hom.:

820

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0640

Gnomad ASJ

AF:

0.0683

Gnomad EAS

AF:

0.0613

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.0223

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.0662

Gnomad OTH

AF:

0.0880

GnomAD2 exomes

AF:

0.0808

AC:

20297

AN:

251154

AF XY:

0.0863

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.0446

Gnomad ASJ exome

AF:

0.0693

Gnomad EAS exome

AF:

0.0539

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0653

Gnomad OTH exome

AF:

0.0827

GnomAD4 exome

AF:

0.0713

AC:

104276

AN:

1461840

Hom.:

4971

Cov.:

AF XY:

0.0751

AC XY:

54650

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.161

AC:

5393

AN:

33478

American (AMR)

AF:

0.0469

AC:

2099

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0667

AC:

1744

AN:

26136

East Asian (EAS)

AF:

0.0558

AC:

2213

AN:

39694

South Asian (SAS)

AF:

0.197

AC:

17025

AN:

86254

European-Finnish (FIN)

AF:

0.0246

AC:

1315

AN:

53414

Middle Eastern (MID)

AF:

0.122

AC:

705

AN:

5766

European-Non Finnish (NFE)

AF:

0.0620

AC:

68893

AN:

1111980

Other (OTH)

AF:

0.0810

AC:

4889

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

5502

11003

16505

22006

27508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2678

5356

8034

10712

13390

<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:

0.0915

AC:

13925

AN:

152156

Hom.:

827

Cov.:

AF XY:

0.0916

AC XY:

6815

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.153

AC:

6349

AN:

41482

American (AMR)

AF:

0.0639

AC:

977

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0683

AC:

237

AN:

3468

East Asian (EAS)

AF:

0.0611

AC:

316

AN:

5172

South Asian (SAS)

AF:

0.210

AC:

1008

AN:

4810

European-Finnish (FIN)

AF:

0.0223

AC:

237

AN:

10610

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0662

AC:

4505

AN:

68002

Other (OTH)

AF:

0.0946

AC:

200

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

630

1259

1889

2518

3148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0734

Hom.:

1087

Bravo

AF:

0.0933

Asia WGS

AF:

0.172

AC:

595

AN:

3478

EpiCase

AF:

0.0706

EpiControl

AF:

0.0701

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 24, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal multiple pterygium syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital myasthenic syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

4.8

Mutation Taster

=84/16

polymorphism (auto)

(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

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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