2-232543573-C-T

Position:

• chr2-232543573-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 259670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232543573-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
CHRNG	NM_005199.5	c.921-12C>T		intron_variant		ENST00000651502.1	NP_005190.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1	c.921-12C>T		intron_variant			NM_005199.5	ENSP00000498757.1
CHRNG	ENST00000389492.3	c.765-12C>T		intron_variant		1		ENSP00000374143.3

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36277 AN: 151910 Hom.: 5065 Cov.: 32

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

GnomAD3 exomes AF: 0.309 AC: 76913 AN: 248804 Hom.: 13213 AF XY: 0.311 AC XY: 41747 AN XY: 134432

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 SAS exome AF: 0.375

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.: 26 AF XY: 0.277 AC XY: 195936 AN XY: 706378

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.464

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.239 AC: 36321 AN: 152028 Hom.: 5087 Cov.: 32 AF XY: 0.244 AC XY: 18092 AN XY: 74282

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.230

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.266

Alfa AF: 0.226 Hom.: 1636

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

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Autosomal recessive multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.5
DANN	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs13018423; hg19: chr2-233408283; COSMIC: COSV67315333; COSMIC: COSV67315333;