2-232543573-C-T

Variant names:

• chr2-232543573-C-T
• rs13018423
• NM_005199.5:c.921-12C>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.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

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: G2P, Ambry Genetics, 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: 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=-0.62).
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	NM_005199.5	MANE Select	c.921-12C>T		intron	N/A	NP_005190.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.921-12C>T		intron	N/A	ENSP00000498757.1	P07510-1
	CHRNG	ENST00000389492.3	TSL:1	c.765-12C>T		intron	N/A	ENSP00000374143.3	P07510-2

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

GnomAD2 exomes AF: 0.309 AC: 76913 AN: 248804 AF XY: 0.311

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

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

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

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: 98 AN: 292

European-Non Finnish (NFE) AF: 0.259 AC: 17577 AN: 67968

Other (OTH) AF: 0.266 AC: 562 AN: 2110

Alfa AF: 0.241 Hom.: 3480

Bravo AF: 0.248

Asia WGS AF: 0.436 AC: 1513 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.5
DANN	Benign	0.81
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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