chr16-28826890-G-A

Position:

• chr16-28826890-G-A

Variant summary

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

The ENST00000336783.9(ATXN2L):​c.645G>A​(p.Met215Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ATXN2L ENST00000336783.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18986738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN2L	NM_007245.4	c.645G>A	p.Met215Ile	missense_variant	6/22	ENST00000336783.9	NP_009176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2L	ENST00000336783.9	c.645G>A	p.Met215Ile	missense_variant	6/22	1	NM_007245.4	ENSP00000338718	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.645G>A (p.M215I) alteration is located in exon 6 (coding exon 6) of the ATXN2L gene. This alteration results from a G to A substitution at nucleotide position 645, causing the methionine (M) at amino acid position 215 to be replaced by an isoleucine (I). 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	0.55
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	.;.;.;T;.;T;.;.
Eigen	Benign	-0.0020
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;N;.;N;.
MutationTaster	Benign	0.71	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.46	N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.053	T;D;D;D;T;D;D;T
Sift4G	Benign	0.091	T;T;T;T;T;T;T;T
Polyphen		0.40	B;B;B;B;.;.;.;.
Vest4		0.66
MutPred		0.28		Loss of ubiquitination at K218 (P = 0.0439);Loss of ubiquitination at K218 (P = 0.0439);Loss of ubiquitination at K218 (P = 0.0439);Loss of ubiquitination at K218 (P = 0.0439);Loss of ubiquitination at K218 (P = 0.0439);Loss of ubiquitination at K218 (P = 0.0439);Loss of ubiquitination at K218 (P = 0.0439);.;
MVP		0.44
MPC		0.69
ClinPred		0.67	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-28838211;