rs2229194

Positions:

• chr2-232533988-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000751.3(CHRND):​c.1105C>T​(p.Pro369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,814 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P369R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (6 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.52

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058621466).
• BP6: Variant 2-232533988-C-T is Benign according to our data. Variant chr2-232533988-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193603.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}. Variant chr2-232533988-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00293 (447/152362) while in subpopulation AMR AF= 0.00621 (95/15310). AF 95% confidence interval is 0.0052. There are 2 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRND	NM_000751.3	c.1105C>T	p.Pro369Ser	missense_variant	10/12	ENST00000258385.8
CHRND	NM_001256657.2	c.1060C>T	p.Pro354Ser	missense_variant	9/11
CHRND	NM_001311196.2	c.802C>T	p.Pro268Ser	missense_variant	10/12
CHRND	NM_001311195.2	c.523C>T	p.Pro175Ser	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.1105C>T	p.Pro369Ser	missense_variant	10/12	1	NM_000751.3	P1
CHRND	ENST00000543200.5	c.1060C>T	p.Pro354Ser	missense_variant	9/11	2
CHRND	ENST00000441621.6	c.*287C>T		3_prime_UTR_variant, NMD_transcript_variant	9/11	5
CHRND	ENST00000446616.1	c.*746C>T		3_prime_UTR_variant, NMD_transcript_variant	10/12	3

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00340 AC: 854 AN: 251092 Hom.: 4 AF XY: 0.00330 AC XY: 448 AN XY: 135822

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00832

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00323 AC: 4725 AN: 1461452 Hom.: 6 Cov.: 32 AF XY: 0.00312 AC XY: 2270 AN XY: 727032

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00713

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00293 AC: 447 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00307 AC XY: 229 AN XY: 74510

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00320 Hom.: 1

Bravo AF: 0.00255

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	CHRND: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Lethal multiple pterygium syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Congenital myasthenic syndrome 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 25, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 06, 2015

- -

Congenital myasthenic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	.;D
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.26
Sift	Benign	0.059	T;D
Sift4G	Uncertain	0.044	D;D
Polyphen		0.93	.;P
Vest4		0.30
MVP		0.96
MPC		0.31
ClinPred		0.036	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229194; hg19: chr2-233398698;