rs41265125

Variant names:

• chr2-232531315-G-A
• rs41265125
• NM_000751.3:c.821-37G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000751.3(CHRND):​c.821-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 1,382,740 control chromosomes in the GnomAD database, including 4,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (364 hom., cov: 29)
  • Exomes 𝑓: 0.081 (4474 hom.)
• Consequence: CHRND NM_000751.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.278
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-232531315-G-A is Benign according to our data. Variant chr2-232531315-G-A is described in ClinVar as Benign. ClinVar VariationId is 256782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0997 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.821-37G>A		intron_variant	Intron 7 of 11	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.776-37G>A		intron_variant	Intron 6 of 10		NP_001243586.1
CHRND	NM_001311196.2	c.518-37G>A		intron_variant	Intron 7 of 11		NP_001298125.1
CHRND	NM_001311195.2	c.239-37G>A		intron_variant	Intron 5 of 9		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.821-37G>A		intron_variant	Intron 7 of 11	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 9007 AN: 125560 Hom.: 364 Cov.: 29

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0668

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0675

Gnomad MID AF: 0.145

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.0838

GnomAD2 exomes AF: 0.0700 AC: 16601 AN: 237190 AF XY: 0.0732

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0422

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0690

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.0817

GnomAD4 exome AF: 0.0811 AC: 102010 AN: 1257068 Hom.: 4474 Cov.: 20 AF XY: 0.0821 AC XY: 51964 AN XY: 633060

African (AFR) AF: 0.0132 AC: 371 AN: 28080

American (AMR) AF: 0.0447 AC: 1963 AN: 43898

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2594 AN: 23798

East Asian (EAS) AF: 0.0175 AC: 664 AN: 37936

South Asian (SAS) AF: 0.0879 AC: 7127 AN: 81076

European-Finnish (FIN) AF: 0.0692 AC: 3362 AN: 48552

Middle Eastern (MID) AF: 0.130 AC: 635 AN: 4880

European-Non Finnish (NFE) AF: 0.0866 AC: 81091 AN: 936154

Other (OTH) AF: 0.0798 AC: 4203 AN: 52694

GnomAD4 genome AF: 0.0716 AC: 9003 AN: 125672 Hom.: 364 Cov.: 29 AF XY: 0.0701 AC XY: 4307 AN XY: 61436

African (AFR) AF: 0.0176 AC: 550 AN: 31218

American (AMR) AF: 0.0667 AC: 888 AN: 13322

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 369 AN: 2774

East Asian (EAS) AF: 0.0122 AC: 59 AN: 4854

South Asian (SAS) AF: 0.108 AC: 424 AN: 3918

European-Finnish (FIN) AF: 0.0675 AC: 584 AN: 8658

Middle Eastern (MID) AF: 0.147 AC: 34 AN: 232

European-Non Finnish (NFE) AF: 0.0996 AC: 5788 AN: 58104

Other (OTH) AF: 0.0827 AC: 144 AN: 1742

Alfa AF: 0.0767 Hom.: 164

Bravo AF: 0.0567

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.83
CADD	Benign	2.4
DANN	Benign	0.58
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41265125; hg19: chr2-233396025;