16-28823308-C-G

Variant names:

• chr16-28823308-C-G
• rs2050260648
• NM_007245.4:c.49C>G

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.49C>G​(p.Pro17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,339,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. P17S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ATXN2L NM_007245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• 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=0.20031768).

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.49C>G	p.Pro17Ala	missense	Exon 1 of 22	NP_009176.2
	ATXN2L	NM_001387166.1		c.49C>G	p.Pro17Ala	missense	Exon 1 of 24	NP_001374095.1
	ATXN2L	NM_001387167.1		c.49C>G	p.Pro17Ala	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.49C>G	p.Pro17Ala	missense	Exon 1 of 22	ENSP00000338718.4	Q8WWM7-1
	ATXN2L	ENST00000395547.6	TSL:1	c.49C>G	p.Pro17Ala	missense	Exon 1 of 24	ENSP00000378917.2	Q8WWM7-3
	ATXN2L	ENST00000564304.5	TSL:1	c.49C>G	p.Pro17Ala	missense	Exon 1 of 23	ENSP00000457613.1	H3BUF6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339032 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 665414

⚠️ 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: 27290

American (AMR) AF: 0.00 AC: 0 AN: 29626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22450

East Asian (EAS) AF: 0.0000319 AC: 1 AN: 31340

South Asian (SAS) AF: 0.00 AC: 0 AN: 72914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3814

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1053866

Other (OTH) AF: 0.00 AC: 0 AN: 54076

⚠️ 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	Benign	0.052
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.076
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.52	P
Vest4		0.30
MutPred		0.19		Loss of glycosylation at P17 (P = 7e-04)
MVP		0.38
MPC		0.48
ClinPred		0.54	D
GERP RS		3.9
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.11
gMVP		0.12

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: rs2050260648; hg19: chr16-28834629;