chr16-28823549-G-A

Variant names:

• chr16-28823549-G-A
• rs986271757
• NM_007245.4:c.290G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007245.4(ATXN2L):​c.290G>A​(p.Gly97Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,203,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G97V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: ATXN2L NM_007245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21806794).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2L	NM_007245.4	MANE Select	c.290G>A	p.Gly97Asp	missense	Exon 1 of 22	NP_009176.2
	ATXN2L	NM_001387166.1		c.290G>A	p.Gly97Asp	missense	Exon 1 of 24	NP_001374095.1
	ATXN2L	NM_001387167.1		c.290G>A	p.Gly97Asp	missense	Exon 1 of 24	NP_001374096.1	Q8WWM7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2L	ENST00000336783.9	TSL:1 MANE Select	c.290G>A	p.Gly97Asp	missense	Exon 1 of 22	ENSP00000338718.4	Q8WWM7-1
	ATXN2L	ENST00000395547.6	TSL:1	c.290G>A	p.Gly97Asp	missense	Exon 1 of 24	ENSP00000378917.2	Q8WWM7-3
	ATXN2L	ENST00000564304.5	TSL:1	c.290G>A	p.Gly97Asp	missense	Exon 1 of 23	ENSP00000457613.1	H3BUF6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000249 AC: 3 AN: 1203246 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 587094

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23954

American (AMR) AF: 0.0000847 AC: 1 AN: 11806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18384

East Asian (EAS) AF: 0.00 AC: 0 AN: 27234

South Asian (SAS) AF: 0.00 AC: 0 AN: 52508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3360

European-Non Finnish (NFE) AF: 0.00000202 AC: 2 AN: 989118

Other (OTH) AF: 0.00 AC: 0 AN: 48596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.075
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.058
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.35	T
Polyphen		0.91	P
Vest4		0.21
MutPred		0.36		Gain of catalytic residue at G97 (P = 0.0302)
MVP		0.37
MPC		0.79
ClinPred		0.56	D
GERP RS		2.8
PromoterAI		0.0094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.30

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

Other links and lift over

dbSNP: rs986271757; hg19: chr16-28834870;