2-232544358-CCT-C

Position:

• chr2-232544358-CCT-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005199.5(CHRNG):​c.1036-4_1036-3delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,610,966 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: CHRNG NM_005199.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.385

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-232544358-CCT-C is Benign according to our data. Variant chr2-232544358-CCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 335009.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000381 (58/152304) while in subpopulation EAS AF= 0.00444 (23/5180). AF 95% confidence interval is 0.00303. There are 2 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIGD1	NM_145702.4	c.*3747_*3748delAG		3_prime_UTR_variant	1/1	ENST00000408957.7	NP_663748.1
CHRNG	NM_005199.5	c.1036-4_1036-3delCT		splice_region_variant, intron_variant		ENST00000651502.1	NP_005190.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIGD1	ENST00000408957	c.*3747_*3748delAG		3_prime_UTR_variant	1/1		NM_145702.4	ENSP00000386186.3
CHRNG	ENST00000651502.1	c.1036-4_1036-3delCT		splice_region_variant, intron_variant			NM_005199.5	ENSP00000498757.1
CHRNG	ENST00000389492.3	c.880-4_880-3delCT		splice_region_variant, intron_variant		1		ENSP00000374143.3

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000731 AC: 180 AN: 246382 Hom.: 2 AF XY: 0.000739 AC XY: 99 AN XY: 134018

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00311

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00255

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000450 AC: 657 AN: 1458662 Hom.: 4 AF XY: 0.000440 AC XY: 319 AN XY: 725800

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00836

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00262

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.000151

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive multiple pterygium syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -29

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

Publications

LitVar

Other links and lift over

dbSNP: rs3217418; hg19: chr2-233409068;