chr2-232545584-C-T

Variant names:

• chr2-232545584-C-T
• rs2099489
• NM_005199.5:c.1422C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005199.5(CHRNG):​c.1422C>T​(p.Arg474Arg) 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:7
• Conservation: PhyloP100: -3.64
• Publications: 11 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]

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

Our verdict: Benign. The variant received -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 VariationId is 194064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1422C>T	p.Arg474Arg	synonymous	Exon 12 of 12	NP_005190.4
	TIGD1	NM_145702.4	MANE Select	c.*2523G>A		3_prime_UTR	Exon 1 of 1	NP_663748.1	Q96MW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.1422C>T	p.Arg474Arg	synonymous	Exon 12 of 12	ENSP00000498757.1	P07510-1
	CHRNG	ENST00000389492.3	TSL:1	c.1266C>T	p.Arg422Arg	synonymous	Exon 11 of 11	ENSP00000374143.3	P07510-2
	TIGD1	ENST00000408957.7	TSL:6 MANE Select	c.*2523G>A		3_prime_UTR	Exon 1 of 1	ENSP00000386186.3	Q96MW7

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

GnomAD2 exomes AF: 0.187 AC: 46845 AN: 250646 AF XY: 0.191

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 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

African (AFR) AF: 0.125 AC: 4201 AN: 33480

American (AMR) AF: 0.160 AC: 7136 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6366 AN: 26136

East Asian (EAS) AF: 0.104 AC: 4119 AN: 39700

South Asian (SAS) AF: 0.213 AC: 18343 AN: 86250

European-Finnish (FIN) AF: 0.205 AC: 10909 AN: 53270

Middle Eastern (MID) AF: 0.236 AC: 1362 AN: 5768

European-Non Finnish (NFE) AF: 0.205 AC: 227714 AN: 1111876

Other (OTH) AF: 0.198 AC: 11964 AN: 60388

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

African (AFR) AF: 0.121 AC: 5006 AN: 41518

American (AMR) AF: 0.189 AC: 2890 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3468

East Asian (EAS) AF: 0.106 AC: 547 AN: 5176

South Asian (SAS) AF: 0.214 AC: 1032 AN: 4822

European-Finnish (FIN) AF: 0.200 AC: 2115 AN: 10590

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13766 AN: 67968

Other (OTH) AF: 0.190 AC: 400 AN: 2108

Alfa AF: 0.195 Hom.: 12506

Bravo AF: 0.170

Asia WGS AF: 0.147 AC: 512 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.204

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive multiple pterygium syndrome (1)
-	-	1	Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.061
DANN	Benign	0.89
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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