rs367936158

Variant names:

• chr2-232528975-C-A
• rs367936158
• NM_000751.3:c.619+4C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000751.3(CHRND):​c.619+4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,611,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: CHRND NM_000751.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004704
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.332
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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.619+4C>A		splice_region intron	N/A	NP_000742.1
	CHRND	NM_001256657.2		c.574+4C>A		splice_region intron	N/A	NP_001243586.1
	CHRND	NM_001311196.2		c.316+4C>A		splice_region intron	N/A	NP_001298125.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.619+4C>A		splice_region intron	N/A	ENSP00000258385.3
	CHRND	ENST00000543200.5	TSL:2	c.574+4C>A		splice_region intron	N/A	ENSP00000438380.1
	CHRND	ENST00000412233.5	TSL:4	n.509+319C>A		intron	N/A	ENSP00000398143.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152172 Hom.: 0 Cov.: 32

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: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000320 AC: 80 AN: 250282 AF XY: 0.000303

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000428 AC: 624 AN: 1459114 Hom.: 0 Cov.: 31 AF XY: 0.000399 AC XY: 290 AN XY: 726042

African (AFR) AF: 0.0000897 AC: 3 AN: 33442

American (AMR) AF: 0.000447 AC: 20 AN: 44714

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00145 AC: 77 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000451 AC: 501 AN: 1109714

Other (OTH) AF: 0.000381 AC: 23 AN: 60302

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68034

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000394 Hom.: 0

Bravo AF: 0.000230

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal multiple pterygium syndrome Uncertain:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 6 of the CHRND gene. It does not directly change the encoded amino acid sequence of the CHRND protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367936158, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CHRND-related conditions. ClinVar contains an entry for this variant (Variation ID: 534530). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

CHRND-related disorder Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		0.33
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.13
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: rs367936158; hg19: chr2-233393685;