rs547149375

Variant names:

• chr2-232525995-C-T
• rs547149375
• ENST00000441621.6:n.-221C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000441621.6(CHRND):​n.-221C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 474,730 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 29)
  • Exomes 𝑓: 0.014 (125 hom.)
• Consequence: CHRND ENST00000441621.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0860
• Publications: 1 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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• congenital myasthenic syndrome 3C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.027 (4096/151636) while in subpopulation NFE AF = 0.041 (2777/67766). AF 95% confidence interval is 0.0397. There are 85 homozygotes in GnomAd4. There are 2056 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 85 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.-221C>T		upstream_gene_variant		ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.-221C>T		upstream_gene_variant			NP_001243586.1
CHRND	NM_001311196.2	c.-492C>T		upstream_gene_variant			NP_001298125.1
CHRND	NM_001311195.2	c.-492C>T		upstream_gene_variant			NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.-221C>T		upstream_gene_variant		1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4095 AN: 151526 Hom.: 85 Cov.: 29

Gnomad AFR AF: 0.00611

Gnomad AMI AF: 0.0133

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0227

GnomAD4 exome AF: 0.0139 AC: 4482 AN: 323094 Hom.: 125 Cov.: 3 AF XY: 0.0134 AC XY: 2301 AN XY: 171080

African (AFR) AF: 0.00270 AC: 23 AN: 8534

American (AMR) AF: 0.00359 AC: 41 AN: 11418

Ashkenazi Jewish (ASJ) AF: 0.00824 AC: 83 AN: 10068

East Asian (EAS) AF: 0.0000452 AC: 1 AN: 22104

South Asian (SAS) AF: 0.00596 AC: 188 AN: 31548

European-Finnish (FIN) AF: 0.0265 AC: 566 AN: 21380

Middle Eastern (MID) AF: 0.00134 AC: 2 AN: 1490

European-Non Finnish (NFE) AF: 0.0170 AC: 3350 AN: 197606

Other (OTH) AF: 0.0120 AC: 228 AN: 18946

GnomAD4 genome AF: 0.0270 AC: 4096 AN: 151636 Hom.: 85 Cov.: 29 AF XY: 0.0278 AC XY: 2056 AN XY: 74078

African (AFR) AF: 0.00609 AC: 252 AN: 41386

American (AMR) AF: 0.0156 AC: 238 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3464

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5104

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4806

European-Finnish (FIN) AF: 0.0617 AC: 651 AN: 10548

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2777 AN: 67766

Other (OTH) AF: 0.0224 AC: 47 AN: 2094

Alfa AF: 0.0263 Hom.: 24

Bravo AF: 0.0223

Asia WGS AF: 0.00725 AC: 25 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.79
PhyloP100		-0.086
PromoterAI		-0.064	Neutral

Splicing

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

Other links and lift over

dbSNP: rs547149375; hg19: chr2-233390705; COSMIC: COSV51318370;