2-232539880-G-C

Variant names:

• chr2-232539880-G-C
• rs12996322
• NM_005199.5:c.55+78G>C

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.55+78G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,608,468 control chromosomes in the GnomAD database, including 99,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8006 hom., cov: 33)
  • Exomes 𝑓: 0.35 (91225 hom.)
• Consequence: CHRNG NM_005199.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.59
• 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=-0.91).
• BP6: Variant 2-232539880-G-C is Benign according to our data. Variant chr2-232539880-G-C is described in ClinVar as Benign. ClinVar VariationId is 1290181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.437 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.55+78G>C		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.55+78G>C		intron	N/A	ENSP00000498757.1
	CHRNG	ENST00000389492.3	TSL:1	c.55+78G>C		intron	N/A	ENSP00000374143.3
	CHRNG	ENST00000485094.1	TSL:1	n.76+78G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47073 AN: 151940 Hom.: 7988 Cov.: 33

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.318

GnomAD4 exome AF: 0.349 AC: 507960 AN: 1456410 Hom.: 91225 Cov.: 33 AF XY: 0.350 AC XY: 253833 AN XY: 724526

African (AFR) AF: 0.168 AC: 5589 AN: 33350

American (AMR) AF: 0.544 AC: 24307 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9718 AN: 26078

East Asian (EAS) AF: 0.445 AC: 17630 AN: 39662

South Asian (SAS) AF: 0.407 AC: 35073 AN: 86128

European-Finnish (FIN) AF: 0.303 AC: 16100 AN: 53106

Middle Eastern (MID) AF: 0.327 AC: 1580 AN: 4834

European-Non Finnish (NFE) AF: 0.340 AC: 377264 AN: 1108470

Other (OTH) AF: 0.344 AC: 20699 AN: 60132

GnomAD4 genome AF: 0.310 AC: 47109 AN: 152058 Hom.: 8006 Cov.: 33 AF XY: 0.313 AC XY: 23251 AN XY: 74316

African (AFR) AF: 0.181 AC: 7505 AN: 41514

American (AMR) AF: 0.446 AC: 6809 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1257 AN: 3468

East Asian (EAS) AF: 0.444 AC: 2289 AN: 5158

South Asian (SAS) AF: 0.405 AC: 1950 AN: 4812

European-Finnish (FIN) AF: 0.297 AC: 3145 AN: 10584

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23003 AN: 67926

Other (OTH) AF: 0.325 AC: 685 AN: 2110

Alfa AF: 0.311 Hom.: 962

Bravo AF: 0.319

Asia WGS AF: 0.462 AC: 1607 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.25
DANN	Benign	0.75
PhyloP100		-1.6
PromoterAI		-0.021	Neutral
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: rs12996322; hg19: chr2-233404590; COSMIC: COSV51317482; COSMIC: COSV51317482;