rs3217418

Variant names:

• chr2-232544358-CCT-C
• rs3217418
• NM_145702.4:c.*3747_*3748delAG

Variant summary

Our verdict is Benign. The variant received -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:2
• Conservation: PhyloP100: 0.385
• Publications: 1 publications found

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]

CHRNG Gene-Disease associations (from GenCC):

• autosomal recessive multiple pterygium syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet
• CHRNG-associated hypo-akinesia disorder of prenatal onset

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• transient neonatal myasthenia gravis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 335009.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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
	TIGD1	NM_145702.4	MANE Select	c.*3747_*3748delAG		3_prime_UTR	Exon 1 of 1	NP_663748.1	Q96MW7
	CHRNG	NM_005199.5	MANE Select	c.1036-4_1036-3delCT		splice_region intron	N/A	NP_005190.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIGD1	ENST00000408957.7	TSL:6 MANE Select	c.*3747_*3748delAG		3_prime_UTR	Exon 1 of 1	ENSP00000386186.3	Q96MW7
	CHRNG	ENST00000651502.1	MANE Select	c.1036-4_1036-3delCT		splice_region intron	N/A	ENSP00000498757.1	P07510-1
	CHRNG	ENST00000389492.3	TSL:1	c.880-4_880-3delCT		splice_region intron	N/A	ENSP00000374143.3	P07510-2

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

GnomAD2 exomes AF: 0.000731 AC: 180 AN: 246382 AF XY: 0.000739

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00836 AC: 332 AN: 39692

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86210

European-Finnish (FIN) AF: 0.00262 AC: 137 AN: 52334

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1110140

Other (OTH) AF: 0.000779 AC: 47 AN: 60300

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

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal recessive multiple pterygium syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3217418; hg19: chr2-233409068;