rs998666789

Variant names:

• chr20-45890495-C-A
• rs998666789
• NM_080749.4:c.497G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-45890495-C-A
• chr20-45890495-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.497G>T​(p.Gly166Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G166E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NEURL2 NM_080749.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.06
• Publications: 0 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]

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]

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

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.497G>T	p.Gly166Val	missense	Exon 1 of 2	NP_542787.1	Q9BR09
	NEURL2	NM_001278535.2		c.497G>T	p.Gly166Val	missense	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.497G>T	p.Gly166Val	missense	Exon 1 of 2	ENSP00000361596.4	Q9BR09
	CTSA	ENST00000372484.8	TSL:1	c.-831C>A		5_prime_UTR	Exon 1 of 15	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000677394.1		c.-730C>A		5_prime_UTR	Exon 1 of 16	ENSP00000504790.1	X6R8A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446162 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 717932

African (AFR) AF: 0.0000302 AC: 1 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 43502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 84054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103872

Other (OTH) AF: 0.00 AC: 0 AN: 59710

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.40		Loss of disorder (P = 0.0575)
MVP		0.64
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.87
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs998666789; hg19: chr20-44519134;