16-28826297-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007245.4(ATXN2L):​c.523C>T​(p.Arg175Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ATXN2L
NM_007245.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16447204).
BS2
High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATXN2LNM_007245.4 linkc.523C>T p.Arg175Cys missense_variant Exon 5 of 22 ENST00000336783.9 NP_009176.2 Q8WWM7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATXN2LENST00000336783.9 linkc.523C>T p.Arg175Cys missense_variant Exon 5 of 22 1 NM_007245.4 ENSP00000338718.4 Q8WWM7-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152176
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
27
AN:
251494
Hom.:
0
AF XY:
0.0000883
AC XY:
12
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000752
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000559
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152176
Hom.:
1
Cov.:
32
AF XY:
0.000309
AC XY:
23
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 14, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.523C>T (p.R175C) alteration is located in exon 5 (coding exon 5) of the ATXN2L gene. This alteration results from a C to T substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a cysteine (C). 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
Uncertain
0.41
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.28
.;.;.;T;.;T;.;.;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
1.8
L;L;L;L;L;.;L;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.6
D;D;D;D;D;D;D;D;D
REVEL
Benign
0.18
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;.;.;.;.;.
Vest4
0.27
MutPred
0.31
Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);.;.;
MVP
0.78
MPC
1.6
ClinPred
0.48
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.41
gMVP
0.68

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.

Other links and lift over

dbSNP: rs1163493993; hg19: chr16-28837618; API