2-232532815-T-G

Variant names:

• chr2-232532815-T-G
• rs12466358
• NM_000751.3:c.1048-1116T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000751.3(CHRND):​c.1048-1116T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,120 control chromosomes in the GnomAD database, including 4,566 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 0.23 (4566 hom., cov: 32)
• Consequence: CHRND NM_000751.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312
• Publications: 9 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000751.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	NM_000751.3	MANE Select	c.1048-1116T>G		intron	N/A	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.1003-1116T>G		intron	N/A	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.745-1116T>G		intron	N/A	NP_001298125.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.1048-1116T>G		intron	N/A	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.1003-1116T>G		intron	N/A	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.847-1116T>G		intron	N/A	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34641 AN: 152000 Hom.: 4544 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34679 AN: 152120 Hom.: 4566 Cov.: 32 AF XY: 0.231 AC XY: 17154 AN XY: 74352

African (AFR) AF: 0.107 AC: 4443 AN: 41496

American (AMR) AF: 0.336 AC: 5128 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1020 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1887 AN: 5164

South Asian (SAS) AF: 0.332 AC: 1602 AN: 4820

European-Finnish (FIN) AF: 0.229 AC: 2425 AN: 10600

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17311 AN: 67974

Other (OTH) AF: 0.251 AC: 530 AN: 2110

Alfa AF: 0.225 Hom.: 1702

Bravo AF: 0.235

Asia WGS AF: 0.387 AC: 1343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.71
PhyloP100		0.31
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: rs12466358; hg19: chr2-233397525;