rs201733876

Variant names:

• chr2-232530046-C-T
• rs201733876
• NM_000751.3:c.727C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-232530046-C-T
• chr2-232530046-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000751.3(CHRND):​c.727C>T​(p.Arg243Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 1.80
• Publications: 3 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-232530046-C-T is Benign according to our data. Variant chr2-232530046-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283138.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000414 (63/152294) while in subpopulation AMR AF = 0.00118 (18/15304). AF 95% confidence interval is 0.00076. There are 1 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	NM_000751.3	MANE Select	c.727C>T	p.Arg243Cys	missense	Exon 7 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.682C>T	p.Arg228Cys	missense	Exon 6 of 11	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.424C>T	p.Arg142Cys	missense	Exon 7 of 12	NP_001298125.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.727C>T	p.Arg243Cys	missense	Exon 7 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.682C>T	p.Arg228Cys	missense	Exon 6 of 11	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.619+1075C>T		intron	N/A	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000295 AC: 74 AN: 251254 AF XY: 0.000280

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000280 AC: 409 AN: 1461872 Hom.: 3 Cov.: 32 AF XY: 0.000286 AC XY: 208 AN XY: 727234

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.000196 AC: 218 AN: 1112008

Other (OTH) AF: 0.000530 AC: 32 AN: 60394

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74468

African (AFR) AF: 0.000626 AC: 26 AN: 41560

American (AMR) AF: 0.00118 AC: 18 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	Lethal multiple pterygium syndrome (2)
-	1	-	Congenital myasthenic syndrome (1)
-	1	-	Congenital myasthenic syndrome 3A (1)
-	1	-	Lethal multiple pterygium syndrome;C4225370:Congenital myasthenic syndrome 3C;C4225371:Congenital myasthenic syndrome 3B;C4225372:Congenital myasthenic syndrome 3A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.8
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.61
MVP		1.0
MPC		1.0
ClinPred		0.14	T
GERP RS		5.2
Varity_R		0.48
gMVP		0.74
Mutation Taster		=76/24	polymorphism

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: rs201733876; hg19: chr2-233394756; COSMIC: COSV51320564; COSMIC: COSV51320564;