2-232543573-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005199.5(CHRNG):c.921-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,566,898 control chromosomes in the GnomAD database, including 61,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5087 hom., cov: 32)

Exomes 𝑓: 0.27 ( 56384 hom. )

Consequence

CHRNG
NM_005199.5 intron

Scores

Splicing: ADA: 0.00009861

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.773

Publications

10 publications found

Variant links:

Genes affected

CHRNG (HGNC:1967): (cholinergic receptor nicotinic gamma subunit) The mammalian muscle-type acetylcholine receptor is a transmembrane pentameric glycoprotein with two alpha subunits, one beta, one delta, and one epsilon (in adult skeletal muscle) or gamma (in fetal and denervated muscle) subunit. This gene, which encodes the gamma subunit, is expressed prior to the thirty-third week of gestation in humans. The gamma subunit of the acetylcholine receptor plays a role in neuromuscular organogenesis and ligand binding and disruption of gamma subunit expression prevents the correct localization of the receptor in cell membranes. Mutations in this gene cause Escobar syndrome and a lethal form of multiple pterygium syndrome. Muscle-type acetylcholine receptor is the major antigen in the autoimmune disease myasthenia gravis.[provided by RefSeq, Sep 2009]

CHRNG Gene-Disease associations (from GenCC):

autosomal recessive multiple pterygium syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet
CHRNG-associated hypo-akinesia disorder of prenatal onset
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
lethal multiple pterygium syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
transient neonatal myasthenia gravis
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

CHRNG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 2-232543573-C-T is Benign according to our data. Variant chr2-232543573-C-T is described in ClinVar as Benign. ClinVar VariationId is 259670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNG	NM_005199.5 link	c.921-12C>T		intron_variant	Intron 8 of 11	ENST00000651502.1	NP_005190.4	P07510-1A0A6F7YAP6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1 link	c.921-12C>T		intron_variant	Intron 8 of 11		NM_005199.5	ENSP00000498757.1		P07510-1
CHRNG	ENST00000389492.3 link	c.765-12C>T		intron_variant	Intron 7 of 10	1		ENSP00000374143.3		P07510-2

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36277

AN:

151910

Hom.:

5065

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.361

Gnomad ASJ

AF:

0.333

Gnomad EAS

AF:

0.416

Gnomad SAS

AF:

0.378

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.309

AC:

76913

AN:

248804

AF XY:

0.311

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.474

Gnomad ASJ exome

AF:

0.341

Gnomad EAS exome

AF:

0.443

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.261

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.274

AC:

387189

AN:

1414870

Hom.:

56384

Cov.:

AF XY:

0.277

AC XY:

195936

AN XY:

706378

show subpopulations

African (AFR)

AF:

0.101

AC:

3300

AN:

32584

American (AMR)

AF:

0.464

AC:

20594

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8864

AN:

25864

East Asian (EAS)

AF:

0.446

AC:

17593

AN:

39454

South Asian (SAS)

AF:

0.378

AC:

32202

AN:

85206

European-Finnish (FIN)

AF:

0.230

AC:

12243

AN:

53242

Middle Eastern (MID)

AF:

0.277

AC:

1573

AN:

5678

European-Non Finnish (NFE)

AF:

0.256

AC:

274296

AN:

1069604

Other (OTH)

AF:

0.281

AC:

16524

AN:

58848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

15715

31430

47146

62861

78576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9314

18628

27942

37256

46570

<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:

0.239

AC:

36321

AN:

152028

Hom.:

5087

Cov.:

AF XY:

0.244

AC XY:

18092

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.114

AC:

4749

AN:

41478

American (AMR)

AF:

0.362

AC:

5543

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

1156

AN:

3468

East Asian (EAS)

AF:

0.416

AC:

2128

AN:

5116

South Asian (SAS)

AF:

0.379

AC:

1825

AN:

4820

European-Finnish (FIN)

AF:

0.230

AC:

2430

AN:

10572

Middle Eastern (MID)

AF:

0.336

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.259

AC:

17577

AN:

67968

Other (OTH)

AF:

0.266

AC:

562

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1326

2651

3977

5302

6628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.241

Hom.:

3480

Bravo

AF:

0.248

Asia WGS

AF:

0.436

AC:

1513

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive multiple pterygium syndrome

Benign:1

Jan 12, 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. -

Lethal multiple pterygium syndrome

Benign:1

Jan 12, 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

-0.62

CADD

Benign

3.5

(source)

DANN

Benign

0.81

PhyloP100

-0.77

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000099

dbscSNV1_RF

Benign

0.044

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