rs1553575390

Positions:

• chr2-232534064-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000258385.8(CHRND):​c.1181A>C​(p.Lys394Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRND ENST00000258385.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: 6.00

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40517527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1181A>C	p.Lys394Thr	missense_variant	10/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1136A>C	p.Lys379Thr	missense_variant	9/11		NP_001243586.1
CHRND	NM_001311196.2	c.878A>C	p.Lys293Thr	missense_variant	10/12		NP_001298125.1
CHRND	NM_001311195.2	c.599A>C	p.Lys200Thr	missense_variant	8/10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1181A>C	p.Lys394Thr	missense_variant	10/12	1	NM_000751.3	ENSP00000258385	P1
CHRND	ENST00000543200.5	c.1136A>C	p.Lys379Thr	missense_variant	9/11	2		ENSP00000438380
CHRND	ENST00000441621.6	c.*363A>C		3_prime_UTR_variant, NMD_transcript_variant	9/11	5		ENSP00000408819
CHRND	ENST00000446616.1	c.*822A>C		3_prime_UTR_variant, NMD_transcript_variant	10/12	3		ENSP00000410801

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Congenital myasthenic syndrome 3C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Congenital myasthenic syndrome 3B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Congenital myasthenic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.61
Sift	Benign	0.078	T;T
Sift4G	Uncertain	0.060	T;T
Polyphen		1.0	.;D
Vest4		0.36
MutPred		0.44		.;Loss of ubiquitination at K394 (P = 0.0047);
MVP		0.99
MPC		0.96
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553575390; hg19: chr2-233398774;