2-232535288-C-A

Variant names:

• chr2-232535288-C-A
• rs114463490
• NM_000751.3:c.1530C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000751.3(CHRND):​c.1530C>A​(p.Asn510Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N510D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.24
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041630805).

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.1530C>A	p.Asn510Lys	missense	Exon 12 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.1485C>A	p.Asn495Lys	missense	Exon 11 of 11	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.1227C>A	p.Asn409Lys	missense	Exon 12 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.1530C>A	p.Asn510Lys	missense	Exon 12 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.1485C>A	p.Asn495Lys	missense	Exon 11 of 11	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.1329C>A	p.Asn443Lys	missense	Exon 11 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0010
DANN	Benign	0.66
DEOGEN2	Benign	0.062	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-4.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.21
Sift	Benign	0.93	T
Sift4G	Benign	0.96	T
Polyphen		0.013	B
Vest4		0.057
MutPred		0.30		Gain of ubiquitination at N510 (P = 0.006)
MVP		0.38
MPC		0.28
ClinPred		0.13	T
GERP RS		-10
Varity_R		0.043
gMVP		0.29
Mutation Taster		=87/13	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: rs114463490; hg19: chr2-233399998;