2-232534087-G-C

Position:

• chr2-232534087-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000751.3(CHRND):​c.1204G>C​(p.Glu402Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E402K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-232534087-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1204G>C	p.Glu402Gln	missense_variant	10/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1159G>C	p.Glu387Gln	missense_variant	9/11		NP_001243586.1
CHRND	NM_001311196.2	c.901G>C	p.Glu301Gln	missense_variant	10/12		NP_001298125.1
CHRND	NM_001311195.2	c.622G>C	p.Glu208Gln	missense_variant	8/10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1204G>C	p.Glu402Gln	missense_variant	10/12	1	NM_000751.3	ENSP00000258385	P1
CHRND	ENST00000543200.5	c.1159G>C	p.Glu387Gln	missense_variant	9/11	2		ENSP00000438380
CHRND	ENST00000441621.6	c.*386G>C		3_prime_UTR_variant, NMD_transcript_variant	9/11	5		ENSP00000408819
CHRND	ENST00000446616.1	c.*845G>C		3_prime_UTR_variant, NMD_transcript_variant	10/12	3		ENSP00000410801

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251358 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.14	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	.;D
Vest4		0.49
MutPred		0.44		.;Gain of MoRF binding (P = 0.0221);
MVP		0.99
MPC		0.85
ClinPred		0.59	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145955590; hg19: chr2-233398797;