chr20-45891103-G-A

Position:

• chr20-45891103-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080749.4(NEURL2):​c.-112C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,207,748 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (75 hom., cov: 33)
  • Exomes 𝑓: 0.020 (651 hom.)
• Consequence: NEURL2 NM_080749.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.771

Genes affected

NEURL2 (HGNC:16156): (neuralized E3 ubiquitin protein ligase 2) This gene encodes a protein that is involved in the regulation of myofibril organization. This protein is likely the adaptor component of the E3 ubiquitin ligase complex in striated muscle, and it regulates the ubiquitin-mediated degradation of beta-catenin during myogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2013]

CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 20-45891103-G-A is Benign according to our data. Variant chr20-45891103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 338519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEURL2	NM_080749.4	c.-112C>T		5_prime_UTR_variant	1/2	ENST00000372518.5
NEURL2	NM_001278535.2	c.-112C>T		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEURL2	ENST00000372518.5	c.-112C>T		5_prime_UTR_variant	1/2	1	NM_080749.4	P1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2688 AN: 152108 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.0203 AC: 21435 AN: 1055522 Hom.: 651 Cov.: 14 AF XY: 0.0235 AC XY: 12232 AN XY: 520308

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0916

Gnomad4 EAS exome AF: 0.0234

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.00188

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0305

GnomAD4 genome AF: 0.0176 AC: 2686 AN: 152226 Hom.: 75 Cov.: 33 AF XY: 0.0188 AC XY: 1397 AN XY: 74432

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.0957

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0137 Hom.: 4

Bravo AF: 0.0158

ClinVar

Significance: 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	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined deficiency of sialidase AND beta galactosidase Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.2
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117529875; hg19: chr20-44519742;