rs150038641

Variant names:

• chr20-45890252-C-G
• rs150038641
• NM_080749.4:c.740G>C

Your query was ambiguous. Multiple possible variants found:

• chr20-45890252-C-G
• chr20-45890252-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_080749.4(NEURL2):​c.740G>C​(p.Gly247Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G247D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEURL2 NM_080749.4 missense, splice_region
• Scores: Splicing: ADA: 0.9862
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.05
• Publications: 2 publications found

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]

SPATA25 (HGNC:16158): (spermatogenesis associated 25) Involved in spermatogenesis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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]

CTSA Gene-Disease associations (from GenCC):

• galactosialidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080749.4. 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
	NEURL2	NM_080749.4	MANE Select	c.740G>C	p.Gly247Ala	missense splice_region	Exon 1 of 2	NP_542787.1	Q9BR09
	NEURL2	NM_001278535.2		c.740G>C	p.Gly247Ala	missense splice_region	Exon 1 of 2	NP_001265464.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEURL2	ENST00000372518.5	TSL:1 MANE Select	c.740G>C	p.Gly247Ala	missense splice_region	Exon 1 of 2	ENSP00000361596.4	Q9BR09
	NEURL2	ENST00000545238.1	TSL:3	c.224G>C	p.Gly75Ala	missense splice_region	Exon 1 of 2	ENSP00000442383.1	H0YGA6
	CTSA	ENST00000606788.5	TSL:2	n.-1074C>G		non_coding_transcript_exon	Exon 1 of 15	ENSP00000476235.1	U3KQU6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248322 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461556 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 727076

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Benign	0.19	T
Sift4G	Benign	0.51	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.43		Loss of catalytic residue at G247 (P = 0.0057)
MVP		0.58
MPC		0.84
ClinPred		0.55	D
GERP RS		4.8
PromoterAI		-0.0086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.74
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
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: rs150038641; hg19: chr20-44518891;