2-232535364-A-G

Variant names:

• chr2-232535364-A-G
• rs2767
• NM_000751.3:c.*52A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000751.3(CHRND):​c.*52A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,597,770 control chromosomes in the GnomAD database, including 115,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10308 hom., cov: 32)
  • Exomes 𝑓: 0.37 (104932 hom.)
• Consequence: CHRND NM_000751.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.936
• Publications: 25 publications found

Genes affected

CHRND (HGNC:1965): (cholinergic receptor nicotinic delta subunit) The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

CHRND Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 3A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• congenital myasthenic syndrome 3C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-232535364-A-G is Benign according to our data. Variant chr2-232535364-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 334975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000751.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	NM_000751.3	MANE Select	c.*52A>G		3_prime_UTR	Exon 12 of 12	NP_000742.1
	CHRND	NM_001256657.2		c.*52A>G		3_prime_UTR	Exon 11 of 11	NP_001243586.1
	CHRND	NM_001311196.2		c.*52A>G		3_prime_UTR	Exon 12 of 12	NP_001298125.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.*52A>G		3_prime_UTR	Exon 12 of 12	ENSP00000258385.3
	CHRND	ENST00000441621.6	TSL:5	n.*788A>G		non_coding_transcript_exon	Exon 11 of 11	ENSP00000408819.2
	CHRND	ENST00000543200.5	TSL:2	c.*52A>G		3_prime_UTR	Exon 11 of 11	ENSP00000438380.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54369 AN: 151962 Hom.: 10286 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.417 AC: 100435 AN: 241134 AF XY: 0.411

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.627

Gnomad ASJ exome AF: 0.372

Gnomad EAS exome AF: 0.553

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.375 AC: 541608 AN: 1445690 Hom.: 104932 Cov.: 30 AF XY: 0.376 AC XY: 270566 AN XY: 719930

African (AFR) AF: 0.266 AC: 8864 AN: 33332

American (AMR) AF: 0.615 AC: 27473 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 9711 AN: 26100

East Asian (EAS) AF: 0.558 AC: 22119 AN: 39658

South Asian (SAS) AF: 0.434 AC: 37376 AN: 86102

European-Finnish (FIN) AF: 0.335 AC: 14629 AN: 43668

Middle Eastern (MID) AF: 0.349 AC: 1989 AN: 5706

European-Non Finnish (NFE) AF: 0.359 AC: 396707 AN: 1106358

Other (OTH) AF: 0.378 AC: 22740 AN: 60126

GnomAD4 genome AF: 0.358 AC: 54429 AN: 152080 Hom.: 10308 Cov.: 32 AF XY: 0.360 AC XY: 26776 AN XY: 74342

African (AFR) AF: 0.280 AC: 11607 AN: 41472

American (AMR) AF: 0.500 AC: 7640 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1253 AN: 3470

East Asian (EAS) AF: 0.548 AC: 2834 AN: 5168

South Asian (SAS) AF: 0.431 AC: 2074 AN: 4816

European-Finnish (FIN) AF: 0.331 AC: 3504 AN: 10598

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24253 AN: 67958

Other (OTH) AF: 0.375 AC: 790 AN: 2108

Alfa AF: 0.366 Hom.: 25735

Bravo AF: 0.372

Asia WGS AF: 0.522 AC: 1815 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive multiple pterygium syndrome Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital Myasthenic Syndrome, Dominant/Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lethal multiple pterygium syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Congenital myasthenic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.61
DANN	Benign	0.29
PhyloP100		-0.94
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: rs2767; hg19: chr2-233400074; COSMIC: COSV51318184; COSMIC: COSV51318184;