2-232525995-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000441621.6(CHRND):c.-221C>T variant causes a 5 prime UTR, NMD transcript 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 29)
  • Exomes 𝑓: 0.014 (125 hom.)
• Consequence: CHRND ENST00000441621.6 5_prime_UTR, NMD_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0860

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-232525995-C-T is Benign according to our data. Variant chr2-232525995-C-T is described in ClinVar as [Benign]. Clinvar id is 1247861.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 85 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000441621.6	c.-221C>T		5_prime_UTR_variant, NMD_transcript_variant	1/11	5

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

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.00359

Gnomad4 ASJ exome AF: 0.00824

Gnomad4 EAS exome AF: 0.0000452

Gnomad4 SAS exome AF: 0.00596

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0120

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

Gnomad4 AFR AF: 0.00609

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0617

Gnomad4 NFE AF: 0.0410

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0399 Hom.: 23

Bravo AF: 0.0223

Asia WGS AF: 0.00725 AC: 25 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	4.3
Dann	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

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