rs71421651

chr2-232545678-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005199.5(CHRNG):c.1516C>T(p.Pro506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0081 in 1,614,182 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P506P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (74 hom.)
• Consequence: CHRNG NM_005199.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.00

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008921087).
• BP6: Variant 2-232545678-C-T is Benign according to our data. Variant chr2-232545678-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235605.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00536 (817/152328) while in subpopulation SAS AF= 0.00932 (45/4828). AF 95% confidence interval is 0.00804. There are 4 homozygotes in gnomad4. There are 345 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNG	NM_005199.5	c.1516C>T	p.Pro506Ser	missense_variant	12/12	ENST00000651502.1
TIGD1	NM_145702.4	c.*2429G>A		3_prime_UTR_variant	1/1	ENST00000408957.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNG	ENST00000651502.1	c.1516C>T	p.Pro506Ser	missense_variant	12/12		NM_005199.5	P1
CHRNG	ENST00000389492.3	c.1360C>T	p.Pro454Ser	missense_variant	11/11	1
TIGD1	ENST00000408957.7	c.*2429G>A		3_prime_UTR_variant	1/1		NM_145702.4	P1

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 816 AN: 152210 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00861

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00672 AC: 1688 AN: 251260 Hom.: 12 AF XY: 0.00730 AC XY: 992 AN XY: 135832

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.00449

Gnomad NFE exome AF: 0.00914

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00839 AC: 12265 AN: 1461854 Hom.: 74 Cov.: 32 AF XY: 0.00851 AC XY: 6191 AN XY: 727228

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00585

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00554

Gnomad4 NFE exome AF: 0.00922

Gnomad4 OTH exome AF: 0.00753

GnomAD4 genome AF: 0.00536 AC: 817 AN: 152328 Hom.: 4 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74488

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00861

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00824 Hom.: 7

Bravo AF: 0.00517

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00678 AC: 823

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CHRNG: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive multiple pterygium syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

CHRNG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lethal multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Uncertain	0.033	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.41
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.051	T;T
Polyphen		0.36	B;.
Vest4		0.13
MVP		0.85
MPC		0.33
ClinPred		0.029	T
GERP RS		4.5
Varity_R		0.29

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: rs71421651; hg19: chr2-233410388; COSMIC: COSV99033462; COSMIC: COSV99033462;