2-232543748-C-T

Variant names:

• chr2-232543748-C-T
• rs73995686
• NM_005199.5:c.1035+49C>T

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.1035+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,144,696 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (84 hom., cov: 32)
  • Exomes 𝑓: 0.025 (569 hom.)
• Consequence: CHRNG NM_005199.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.00
• 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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-232543748-C-T is Benign according to our data. Variant chr2-232543748-C-T is described in ClinVar as Benign. ClinVar VariationId is 259664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNG	NM_005199.5	c.1035+49C>T		intron_variant	Intron 9 of 11	ENST00000651502.1	NP_005190.4
TIGD1	NM_145702.4	c.*4359G>A		downstream_gene_variant		ENST00000408957.7	NP_663748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1	c.1035+49C>T		intron_variant	Intron 9 of 11		NM_005199.5	ENSP00000498757.1
CHRNG	ENST00000389492.3	c.879+49C>T		intron_variant	Intron 8 of 10	1		ENSP00000374143.3
TIGD1	ENST00000408957.7	c.*4359G>A		downstream_gene_variant		6	NM_145702.4	ENSP00000386186.3

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3450 AN: 152158 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0316 AC: 7338 AN: 232476 AF XY: 0.0299

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0674

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.0779

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0246 AC: 24393 AN: 992420 Hom.: 569 Cov.: 13 AF XY: 0.0245 AC XY: 12554 AN XY: 512782

African (AFR) AF: 0.0107 AC: 261 AN: 24442

American (AMR) AF: 0.0639 AC: 2729 AN: 42688

Ashkenazi Jewish (ASJ) AF: 0.00695 AC: 161 AN: 23150

East Asian (EAS) AF: 0.104 AC: 3888 AN: 37312

South Asian (SAS) AF: 0.0286 AC: 2181 AN: 76294

European-Finnish (FIN) AF: 0.0323 AC: 1572 AN: 48596

Middle Eastern (MID) AF: 0.0207 AC: 101 AN: 4874

European-Non Finnish (NFE) AF: 0.0178 AC: 12275 AN: 690152

Other (OTH) AF: 0.0273 AC: 1225 AN: 44912

GnomAD4 genome AF: 0.0227 AC: 3453 AN: 152276 Hom.: 84 Cov.: 32 AF XY: 0.0234 AC XY: 1739 AN XY: 74434

African (AFR) AF: 0.0119 AC: 496 AN: 41564

American (AMR) AF: 0.0415 AC: 636 AN: 15308

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

East Asian (EAS) AF: 0.0989 AC: 510 AN: 5158

South Asian (SAS) AF: 0.0294 AC: 142 AN: 4824

European-Finnish (FIN) AF: 0.0331 AC: 351 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0181 AC: 1234 AN: 68020

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0108 Hom.: 3

Bravo AF: 0.0241

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.69
PhyloP100		-1.0
Mutation Taster		=100/0	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: rs73995686; hg19: chr2-233408458; COSMIC: COSV67316183; COSMIC: COSV67316183;