rs144545619

Positions:

• chr2-232534216-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000751.3(CHRND):​c.1253-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,614,156 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (7 hom.)
• Consequence: CHRND NM_000751.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004130
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.792

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-232534216-G-A is Benign according to our data. Variant chr2-232534216-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00511 (779/152306) while in subpopulation AFR AF= 0.0175 (727/41570). AF 95% confidence interval is 0.0164. There are 6 homozygotes in gnomad4. There are 350 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1253-8G>A		splice_region_variant, intron_variant		ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1208-8G>A		splice_region_variant, intron_variant			NP_001243586.1
CHRND	NM_001311196.2	c.950-8G>A		splice_region_variant, intron_variant			NP_001298125.1
CHRND	NM_001311195.2	c.671-8G>A		splice_region_variant, intron_variant			NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1253-8G>A		splice_region_variant, intron_variant		1	NM_000751.3	ENSP00000258385.3
CHRND	ENST00000543200.5	c.1208-8G>A		splice_region_variant, intron_variant		2		ENSP00000438380.1
CHRND	ENST00000441621.6	n.*435-8G>A		splice_region_variant, intron_variant		5		ENSP00000408819.2
CHRND	ENST00000446616.1	n.*894-8G>A		splice_region_variant, intron_variant		3		ENSP00000410801.1

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 766 AN: 152188 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00146 AC: 368 AN: 251348 Hom.: 5 AF XY: 0.00102 AC XY: 138 AN XY: 135884

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000584 AC: 853 AN: 1461850 Hom.: 7 Cov.: 32 AF XY: 0.000527 AC XY: 383 AN XY: 727224

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00511 AC: 779 AN: 152306 Hom.: 6 Cov.: 33 AF XY: 0.00470 AC XY: 350 AN XY: 74470

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00277 Hom.: 3

Bravo AF: 0.00577

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Lethal multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.85
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0060
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: rs144545619; hg19: chr2-233398926;