rs2278478

Variant names:

• chr2-232526753-A-G
• rs2278478
• NM_000751.3:c.198+79A>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.198+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,510,956 control chromosomes in the GnomAD database, including 60,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4979 hom., cov: 32)
  • Exomes 𝑓: 0.28 (55905 hom.)
• Consequence: CHRND NM_000751.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.89
• Publications: 7 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=-0.89).
• BP6: Variant 2-232526753-A-G is Benign according to our data. Variant chr2-232526753-A-G is described in ClinVar as Benign. ClinVar VariationId is 680135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.198+79A>G		intron_variant	Intron 2 of 11	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.198+79A>G		intron_variant	Intron 2 of 10		NP_001243586.1
CHRND	NM_001311196.2	c.-74+79A>G		intron_variant	Intron 2 of 11		NP_001298125.1
CHRND	NM_001311195.2	c.-74+79A>G		intron_variant	Intron 2 of 9		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.198+79A>G		intron_variant	Intron 2 of 11	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36013 AN: 152000 Hom.: 4956 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.282 AC: 383116 AN: 1358838 Hom.: 55905 AF XY: 0.284 AC XY: 192967 AN XY: 678310

African (AFR) AF: 0.0934 AC: 2910 AN: 31172

American (AMR) AF: 0.443 AC: 19073 AN: 43010

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 7855 AN: 25142

East Asian (EAS) AF: 0.364 AC: 14076 AN: 38710

South Asian (SAS) AF: 0.354 AC: 29381 AN: 83044

European-Finnish (FIN) AF: 0.241 AC: 12346 AN: 51262

Middle Eastern (MID) AF: 0.257 AC: 1378 AN: 5354

European-Non Finnish (NFE) AF: 0.274 AC: 280338 AN: 1024330

Other (OTH) AF: 0.277 AC: 15759 AN: 56814

GnomAD4 genome AF: 0.237 AC: 36057 AN: 152118 Hom.: 4979 Cov.: 32 AF XY: 0.240 AC XY: 17851 AN XY: 74362

African (AFR) AF: 0.103 AC: 4284 AN: 41514

American (AMR) AF: 0.338 AC: 5169 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1052 AN: 3470

East Asian (EAS) AF: 0.359 AC: 1849 AN: 5152

South Asian (SAS) AF: 0.359 AC: 1732 AN: 4828

European-Finnish (FIN) AF: 0.238 AC: 2517 AN: 10586

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18572 AN: 67954

Other (OTH) AF: 0.259 AC: 547 AN: 2114

Alfa AF: 0.247 Hom.: 632

Bravo AF: 0.242

Asia WGS AF: 0.395 AC: 1370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.3
DANN	Benign	0.46
PhyloP100		-1.9
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: rs2278478; hg19: chr2-233391463; COSMIC: COSV51317711; COSMIC: COSV51317711;