Variant 16-28823311-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007245.4(ATXN2L):c.52C>A(p.Pro18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000965 in 1,492,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

ATXN2L
NM_007245.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.812

Variant links:

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]

ATXN2L links:

ENSG00000275807 (HGNC:):

ENSG00000275807 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02639398).

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN2L	NM_007245.4 link	c.52C>A	p.Pro18Thr	missense_variant	1/22	ENST00000336783.9	NP_009176.2	Q8WWM7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2L	ENST00000336783.9 link	c.52C>A	p.Pro18Thr	missense_variant	1/22	1	NM_007245.4	ENSP00000338718.4		Q8WWM7-1

Frequencies

GnomAD3 genomes

AF:

0.000461

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000115

AC:

AN:

147230

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

84606

show subpopulations

Gnomad AFR exome

AF:

0.00150

Gnomad AMR exome

AF:

0.0000514

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000648

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000145

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000552

AC:

AN:

1340364

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

666124

show subpopulations

Gnomad4 AFR exome

AF:

0.00223

Gnomad4 AMR exome

AF:

0.0000676

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000955

Gnomad4 SAS exome

AF:

0.0000273

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000111

GnomAD4 genome

AF:

0.000460

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.000582

ESP6500AA

AF:

0.000863

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000170

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.52C>A (p.P18T) alteration is located in exon 1 (coding exon 1) of the ATXN2L gene. This alteration results from a C to A substitution at nucleotide position 52, causing the proline (P) at amino acid position 18 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

Benign

0.067

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

.;.;.;T;.;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.048

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.83

T;T;T;T;T;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.026

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;N;N;.;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.30

N;N;N;N;N;N;N

REVEL

Benign

0.052

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Benign

0.098

T;T;T;T;T;T;T

Polyphen

0.21

B;B;B;B;.;.;.

Vest4

0.24

MVP

0.29

MPC

0.56

ClinPred

0.20

GERP RS

2.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.26

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over