16-28823308-C-T

Variant names:

• chr16-28823308-C-T
• rs2050260648
• NM_007245.4:c.49C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007245.4(ATXN2L):​c.49C>T​(p.Pro17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,339,028 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ATXN2L NM_007245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

Genes affected

ATXN2L (HGNC:31326): (ataxin 2 like) This gene encodes an ataxin type 2 related protein of unknown function. This protein is a member of the spinocerebellar ataxia (SCAs) family, which is associated with a complex group of neurodegenerative disorders. Several alternatively spliced transcripts encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000275807 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23999143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2L	NM_007245.4	c.49C>T	p.Pro17Ser	missense_variant	Exon 1 of 22	ENST00000336783.9	NP_009176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2L	ENST00000336783.9	c.49C>T	p.Pro17Ser	missense_variant	Exon 1 of 22	1	NM_007245.4	ENSP00000338718.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339028 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 665414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000185

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49C>T (p.P17S) alteration is located in exon 1 (coding exon 1) of the ATXN2L gene. This alteration results from a C to T substitution at nucleotide position 49, causing the proline (P) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	.;.;.;T;.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;N;.;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.18	N;N;N;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.76	T;T;T;T;T;T;T
Sift4G	Benign	0.066	T;T;T;T;T;T;T
Polyphen		0.94	P;P;P;P;.;.;.
Vest4		0.27
MutPred		0.24		Loss of catalytic residue at P17 (P = 0.0081);Loss of catalytic residue at P17 (P = 0.0081);Loss of catalytic residue at P17 (P = 0.0081);Loss of catalytic residue at P17 (P = 0.0081);Loss of catalytic residue at P17 (P = 0.0081);Loss of catalytic residue at P17 (P = 0.0081);Loss of catalytic residue at P17 (P = 0.0081);
MVP		0.49
MPC		0.51
ClinPred		0.63	D
GERP RS		3.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.11
gMVP		0.20

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: rs2050260648; hg19: chr16-28834629;