16-28826258-G-A

Variant names:

• chr16-28826258-G-A
• NM_007245.4:c.484G>A

Variant summary

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

The NM_007245.4(ATXN2L):​c.484G>A​(p.Ala162Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATXN2L NM_007245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2L	NM_007245.4	c.484G>A	p.Ala162Thr	missense_variant	Exon 5 of 22	ENST00000336783.9	NP_009176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2L	ENST00000336783.9	c.484G>A	p.Ala162Thr	missense_variant	Exon 5 of 22	1	NM_007245.4	ENSP00000338718.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.484G>A (p.A162T) alteration is located in exon 5 (coding exon 5) of the ATXN2L gene. This alteration results from a G to A substitution at nucleotide position 484, causing the alanine (A) at amino acid position 162 to be replaced by a threonine (T). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	.;.;.;T;.;T;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;.;M;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;D
REVEL	Benign	0.24
Sift	Uncertain	0.012	D;D;D;D;D;D;D;D;T
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.;.;.;.
Vest4		0.87
MutPred		0.42		Gain of phosphorylation at A162 (P = 0.0168);Gain of phosphorylation at A162 (P = 0.0168);Gain of phosphorylation at A162 (P = 0.0168);Gain of phosphorylation at A162 (P = 0.0168);Gain of phosphorylation at A162 (P = 0.0168);Gain of phosphorylation at A162 (P = 0.0168);Gain of phosphorylation at A162 (P = 0.0168);.;.;
MVP		0.56
MPC		1.0
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-28837579;