rs121909504

Positions:

• chr2-232527440-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000751.3(CHRND):​c.238G>A​(p.Glu80Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.17

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 223) in uniprot entity ACHD_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000751.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 2-232527440-G-A is Pathogenic according to our data. Variant chr2-232527440-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18366.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-232527440-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.238G>A	p.Glu80Lys	missense_variant	3/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001311195.2	c.-34G>A		5_prime_UTR_variant	3/10		NP_001298124.1
CHRND	NM_001311196.2	c.-34G>A		5_prime_UTR_variant	3/12		NP_001298125.1
CHRND	NM_001256657.2	c.198+766G>A		intron_variant			NP_001243586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.238G>A	p.Glu80Lys	missense_variant	3/12	1	NM_000751.3	ENSP00000258385	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 3B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.70
Sift	Benign	0.033	D
Sift4G	Benign	0.18	T
Polyphen		0.80	P
Vest4		0.89
MutPred		0.86		Gain of MoRF binding (P = 0.0068);
MVP		0.87
MPC		0.83
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.72
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121909504; hg19: chr2-233392150;