rs11690038

Positions:

• chr2-232545793-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145702.4(TIGD1):​c.*2314A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,512,122 control chromosomes in the GnomAD database, including 764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (87 hom., cov: 32)
  • Exomes 𝑓: 0.023 (677 hom.)
• Consequence: TIGD1 NM_145702.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.420

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-232545793-T-C is Benign according to our data. Variant chr2-232545793-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 335017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNG	NM_005199.5	c.*77T>C		3_prime_UTR_variant	12/12	ENST00000651502.1	NP_005190.4
TIGD1	NM_145702.4	c.*2314A>G		3_prime_UTR_variant	1/1	ENST00000408957.7	NP_663748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIGD1	ENST00000408957.7	c.*2314A>G		3_prime_UTR_variant	1/1		NM_145702.4	ENSP00000386186	P1
CHRNG	ENST00000651502.1	c.*77T>C		3_prime_UTR_variant	12/12		NM_005199.5	ENSP00000498757	P1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3502 AN: 152168 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0235 AC: 31895 AN: 1359836 Hom.: 677 Cov.: 22 AF XY: 0.0235 AC XY: 16024 AN XY: 682444

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0646

Gnomad4 ASJ exome AF: 0.00706

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.0327

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0230 AC: 3504 AN: 152286 Hom.: 87 Cov.: 32 AF XY: 0.0238 AC XY: 1775 AN XY: 74470

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0431

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.0300

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0201 Hom.: 57

Bravo AF: 0.0245

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive multiple pterygium syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs11690038; hg19: chr2-233410503; COSMIC: COSV51472422; COSMIC: COSV51472422;