rs1242056715

Variant names:

• chr2-232534120-C-A
• rs1242056715
• NM_000751.3:c.1237C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232534120-C-A
• chr2-232534120-C-G
• chr2-232534120-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000751.3(CHRND):​c.1237C>A​(p.Arg413Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R413C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55
• Publications: 1 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, PanelApp Australia, 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: Labcorp Genetics (formerly Invitae), Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1237C>A	p.Arg413Ser	missense	Exon 10 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.1192C>A	p.Arg398Ser	missense	Exon 9 of 11	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.934C>A	p.Arg312Ser	missense	Exon 10 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.1237C>A	p.Arg413Ser	missense	Exon 10 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.1192C>A	p.Arg398Ser	missense	Exon 9 of 11	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.1036C>A	p.Arg346Ser	missense	Exon 9 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.57	T
Sift4G	Benign	0.48	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.47		Gain of phosphorylation at R413 (P = 0.0211)
MVP		0.97
MPC		0.93
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.76
Mutation Taster		=20/80	disease causing

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: rs1242056715; hg19: chr2-233398830;