chr2-232539991-G-A

Position:

chr2-232539991-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_005199.5(CHRNG):c.56-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CHRNG
NM_005199.5 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.35

Variant links:

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]

CHRNG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.1, offset of 1, new splice context is: tcacgcctgtctattgcaAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-232539991-G-A is Pathogenic according to our data. Variant chr2-232539991-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1322085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232539991-G-A is described in Lovd as [Pathogenic]. Variant chr2-232539991-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNG	NM_005199.5 linkuse as main transcript	c.56-1G>A		splice_acceptor_variant		ENST00000651502.1	NP_005190.4

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1 linkuse as main transcript	c.56-1G>A	splice_acceptor_variant		NM_005199.5	ENSP00000498757	P1	P07510-1
CHRNG	ENST00000389492.3 linkuse as main transcript	c.56-1G>A	splice_acceptor_variant	1		ENSP00000374143		P07510-2
CHRNG	ENST00000485094.1 linkuse as main transcript	n.77-1G>A	splice_acceptor_variant, non_coding_transcript_variant	1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250678

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 12, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change affects an acceptor splice site in intron 1 of the CHRNG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHRNG are known to be pathogenic (PMID: 16826520). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with multiple pterygium syndrome (PMID: 22167768, 33060286). ClinVar contains an entry for this variant (Variation ID: 1322085). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Benign

0.97

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.86

MutationTaster

Benign

1.0

D;D;D

GERP RS

4.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.44

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over