2-174759341-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4BP6BS1

The NM_000079.4(CHRNA1):c.224G>A(p.Arg75His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 1,614,006 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00077 ( 1 hom. )

Consequence

CHRNA1
NM_000079.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 7.88

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.72157 (below the threshold of 3.09). Trascript score misZ: 1.6771 (below the threshold of 3.09). GenCC associations: The gene is linked to lethal multiple pterygium syndrome, congenital myasthenic syndrome 1A, myasthenic syndrome, congenital, 1B, fast-channel, postsynaptic congenital myasthenic syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.28598222).

BP6

Variant 2-174759341-C-T is Benign according to our data. Variant chr2-174759341-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 332450.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000644 (98/152180) while in subpopulation NFE AF = 0.00115 (78/68008). AF 95% confidence interval is 0.000942. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNA1	NM_000079.4 link	c.224G>A	p.Arg75His	missense_variant	Exon 3 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3 link	c.224G>A	p.Arg75His	missense_variant	Exon 3 of 10		NP_001034612.1
CHRNA1	XM_017003256.2 link	c.245G>A	p.Arg82His	missense_variant	Exon 2 of 9		XP_016858745.1
CHRNA1	XM_017003257.2 link	c.245G>A	p.Arg82His	missense_variant	Exon 2 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9 link	c.224G>A	p.Arg75His	missense_variant	Exon 3 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000453

AC:

114

AN:

251460

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000818

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000771

AC:

1127

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

539

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000957

AC:

1064

AN:

1111950

Other (OTH)

AF:

0.000530

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000644

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41514

American (AMR)

AF:

0.000458

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000901

Hom.:

Bravo

AF:

0.000582

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Nov 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 06, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHRNA1: PP3, BP5, BS1 -

Lethal multiple pterygium syndrome

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

.;T;T;T;T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.29

T;T;T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.7

L;L;.;.;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.19

N;N;N;N;.;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

D;D;T;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;.;D

Polyphen

1.0

.;D;.;.;.;D

Vest4

0.80

MVP

0.84

MPC

1.0

ClinPred

0.16

GERP RS

6.0

Varity_R

0.45

gMVP

0.68

Mutation Taster

=96/4

polymorphism

(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