2-232545584-C-T

Position:

• chr2-232545584-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005199.5(CHRNG):​c.1422C>T​(p.Arg474=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,613,722 control chromosomes in the GnomAD database, including 32,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2590 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29776 hom.)
• Consequence: CHRNG NM_005199.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.64

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]

TIGD1 (HGNC:14523): (tigger transposable element derived 1) The protein encoded by this gene belongs to the tigger subfamily of the pogo superfamily of DNA-mediated transposons in humans. These proteins are related to DNA transposons found in fungi and nematodes, and more distantly to the Tc1 and mariner transposases. They are also very similar to the major mammalian centromere protein B. The exact function of this gene is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-232545584-C-T is Benign according to our data. Variant chr2-232545584-C-T is described in ClinVar as [Benign]. Clinvar id is 194064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232545584-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNG	NM_005199.5	c.1422C>T	p.Arg474=	synonymous_variant	12/12	ENST00000651502.1
TIGD1	NM_145702.4	c.*2523G>A		3_prime_UTR_variant	1/1	ENST00000408957.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNG	ENST00000651502.1	c.1422C>T	p.Arg474=	synonymous_variant	12/12		NM_005199.5	P1
CHRNG	ENST00000389492.3	c.1266C>T	p.Arg422=	synonymous_variant	11/11	1
TIGD1	ENST00000408957.7	c.*2523G>A		3_prime_UTR_variant	1/1		NM_145702.4	P1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26888 AN: 152022 Hom.: 2592 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.187 AC: 46845 AN: 250646 Hom.: 4620 AF XY: 0.191 AC XY: 25879 AN XY: 135556

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.200 AC: 292114 AN: 1461582 Hom.: 29776 Cov.: 34 AF XY: 0.201 AC XY: 145796 AN XY: 727108

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.177 AC: 26870 AN: 152140 Hom.: 2590 Cov.: 32 AF XY: 0.178 AC XY: 13226 AN XY: 74394

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.190

Alfa AF: 0.199 Hom.: 6130

Bravo AF: 0.170

Asia WGS AF: 0.147 AC: 512 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.204

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lethal multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.061
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2099489; hg19: chr2-233410294; COSMIC: COSV51473749; COSMIC: COSV51473749;