rs267606726

Variant names:

• chr2-232540681-T-G
• rs267606726
• NM_005199.5:c.320T>G
• CHRNG p.Val107Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_005199.5(CHRNG):​c.320T>G​(p.Val107Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNG NM_005199.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.12
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet
• transient neonatal myasthenia gravis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-232540681-T-G is Pathogenic according to our data. Variant chr2-232540681-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 18340.Status of the report is criteria_provided_single_submitter, 1 stars.

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.320T>G	p.Val107Gly	missense	Exon 4 of 12	NP_005190.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.320T>G	p.Val107Gly	missense	Exon 4 of 12	ENSP00000498757.1	P07510-1
	CHRNG	ENST00000389492.3	TSL:1	c.320T>G	p.Val107Gly	missense	Exon 4 of 11	ENSP00000374143.3	P07510-2
	CHRNG	ENST00000485094.1	TSL:1	n.341T>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive multiple pterygium syndrome (2)
1	-	-	Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.98
Mutation Taster		=16/84	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs267606726;

hg19: chr2-233405391;