2-232542410-C-T

Variant names:

• chr2-232542410-C-T
• rs2853462
• NM_005199.5:c.507-13C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005199.5(CHRNG):​c.507-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,595,044 control chromosomes in the GnomAD database, including 44,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3377 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40931 hom.)
• Consequence: CHRNG NM_005199.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.533
• Publications: 8 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-232542410-C-T is Benign according to our data. Variant chr2-232542410-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	NM_005199.5	MANE Select	c.507-13C>T		intron	N/A	NP_005190.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.507-13C>T		intron	N/A	ENSP00000498757.1
	CHRNG	ENST00000389492.3	TSL:1	c.351-13C>T		intron	N/A	ENSP00000374143.3

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30362 AN: 151996 Hom.: 3378 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.210 AC: 52136 AN: 247816 AF XY: 0.211

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.233 AC: 336777 AN: 1442930 Hom.: 40931 Cov.: 29 AF XY: 0.231 AC XY: 166278 AN XY: 718788

African (AFR) AF: 0.131 AC: 4331 AN: 33106

American (AMR) AF: 0.111 AC: 4908 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4796 AN: 25964

East Asian (EAS) AF: 0.267 AC: 10585 AN: 39572

South Asian (SAS) AF: 0.154 AC: 13163 AN: 85476

European-Finnish (FIN) AF: 0.275 AC: 14641 AN: 53222

Middle Eastern (MID) AF: 0.143 AC: 817 AN: 5728

European-Non Finnish (NFE) AF: 0.247 AC: 270388 AN: 1095776

Other (OTH) AF: 0.220 AC: 13148 AN: 59716

GnomAD4 genome AF: 0.200 AC: 30371 AN: 152114 Hom.: 3377 Cov.: 32 AF XY: 0.200 AC XY: 14872 AN XY: 74352

African (AFR) AF: 0.128 AC: 5315 AN: 41514

American (AMR) AF: 0.132 AC: 2018 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3470

East Asian (EAS) AF: 0.311 AC: 1599 AN: 5148

South Asian (SAS) AF: 0.154 AC: 742 AN: 4822

European-Finnish (FIN) AF: 0.287 AC: 3040 AN: 10580

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.243 AC: 16510 AN: 67976

Other (OTH) AF: 0.169 AC: 358 AN: 2116

Alfa AF: 0.218 Hom.: 6854

Bravo AF: 0.186

Asia WGS AF: 0.170 AC: 589 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive multiple pterygium syndrome (1)
-	-	1	Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
DANN	Benign	0.55
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2853462; hg19: chr2-233407120; COSMIC: COSV67315569; COSMIC: COSV67315569;