NM_005199.5:c.445G>A

Variant names:

• chr2-232541468-G-A
• rs2289080
• NM_005199.5:c.445G>A

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.445G>A​(p.Ala149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,614,044 control chromosomes in the GnomAD database, including 865 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (103 hom., cov: 32)
  • Exomes 𝑓: 0.024 (762 hom.)
• Consequence: CHRNG NM_005199.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0180
• Publications: 19 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 (MetaRNN=0.0039532185).
• BP6: Variant 2-232541468-G-A is Benign according to our data. Variant chr2-232541468-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.1 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.445G>A	p.Ala149Thr	missense	Exon 5 of 12	NP_005190.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.445G>A	p.Ala149Thr	missense	Exon 5 of 12	ENSP00000498757.1	P07510-1
	CHRNG	ENST00000389492.3	TSL:1	c.350+757G>A		intron	N/A	ENSP00000374143.3	P07510-2
	CHRNG	ENST00000485094.1	TSL:1	n.466G>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4227 AN: 152134 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0335 AC: 8415 AN: 251456 AF XY: 0.0312

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.0688

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.0887

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0239 AC: 34990 AN: 1461792 Hom.: 762 Cov.: 31 AF XY: 0.0239 AC XY: 17368 AN XY: 727208

African (AFR) AF: 0.0272 AC: 910 AN: 33478

American (AMR) AF: 0.0658 AC: 2943 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 185 AN: 26134

East Asian (EAS) AF: 0.114 AC: 4526 AN: 39700

South Asian (SAS) AF: 0.0290 AC: 2503 AN: 86258

European-Finnish (FIN) AF: 0.0331 AC: 1769 AN: 53384

Middle Eastern (MID) AF: 0.0217 AC: 125 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20271 AN: 1111960

Other (OTH) AF: 0.0291 AC: 1758 AN: 60392

GnomAD4 genome AF: 0.0279 AC: 4244 AN: 152252 Hom.: 103 Cov.: 32 AF XY: 0.0285 AC XY: 2121 AN XY: 74432

African (AFR) AF: 0.0286 AC: 1187 AN: 41542

American (AMR) AF: 0.0439 AC: 671 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.108 AC: 558 AN: 5176

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4818

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1239 AN: 68016

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0233 Hom.: 306

Bravo AF: 0.0298

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0320 AC: 3885

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0166

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive multiple pterygium syndrome (2)
-	-	1	Congenital Myasthenic Syndrome, Dominant/Recessive (1)
-	-	1	Lethal multiple pterygium syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.3
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.29	N
PhyloP100		-0.018
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.18
Sift	Benign	0.37	T
Sift4G	Benign	0.44	T
Polyphen		0.010	B
Vest4		0.033
MPC		0.19
ClinPred		0.0099	T
GERP RS		2.3
Varity_R		0.099
Mutation Taster		=94/6	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: rs2289080; hg19: chr2-233406178; COSMIC: COSV101263897; COSMIC: COSV101263897;