rs145857136

Positions:

• chr2-232535174-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_000751.3(CHRND):​c.1416C>T​(p.Leu472=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: CHRND NM_000751.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-232535174-C-T is Benign according to our data. Variant chr2-232535174-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 534534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000413 (63/152362) while in subpopulation AFR AF= 0.00123 (51/41584). AF 95% confidence interval is 0.000958. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1416C>T	p.Leu472=	synonymous_variant	12/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1371C>T	p.Leu457=	synonymous_variant	11/11		NP_001243586.1
CHRND	NM_001311196.2	c.1113C>T	p.Leu371=	synonymous_variant	12/12		NP_001298125.1
CHRND	NM_001311195.2	c.834C>T	p.Leu278=	synonymous_variant	10/10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1416C>T	p.Leu472=	synonymous_variant	12/12	1	NM_000751.3	ENSP00000258385	P1
CHRND	ENST00000543200.5	c.1371C>T	p.Leu457=	synonymous_variant	11/11	2		ENSP00000438380
CHRND	ENST00000441621.6	c.*598C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11	5		ENSP00000408819
CHRND	ENST00000446616.1	c.*1057C>T		3_prime_UTR_variant, NMD_transcript_variant	12/12	3		ENSP00000410801

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251410 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135884

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39 AN XY: 727242

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000413 AC: 63 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74506

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000351

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal multiple pterygium syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs145857136; hg19: chr2-233399884;