16-28823494-C-T

Variant names:

• chr16-28823494-C-T
• rs1004412705
• NM_007245.4:c.235C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_007245.4(ATXN2L):​c.235C>T​(p.Pro79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,382,168 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P79L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ATXN2L NM_007245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.610
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08371219).
• BS2: High AC in GnomAd4 at 27 AD gene.

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.235C>T	p.Pro79Ser	missense	Exon 1 of 22	NP_009176.2
	ATXN2L	NM_001387166.1		c.235C>T	p.Pro79Ser	missense	Exon 1 of 24	NP_001374095.1
	ATXN2L	NM_001387167.1		c.235C>T	p.Pro79Ser	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.235C>T	p.Pro79Ser	missense	Exon 1 of 22	ENSP00000338718.4	Q8WWM7-1
	ATXN2L	ENST00000395547.6	TSL:1	c.235C>T	p.Pro79Ser	missense	Exon 1 of 24	ENSP00000378917.2	Q8WWM7-3
	ATXN2L	ENST00000564304.5	TSL:1	c.235C>T	p.Pro79Ser	missense	Exon 1 of 23	ENSP00000457613.1	H3BUF6

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000478

GnomAD4 exome AF: 0.0000138 AC: 17 AN: 1229940 Hom.: 0 Cov.: 32 AF XY: 0.00000997 AC XY: 6 AN XY: 601912

African (AFR) AF: 0.000651 AC: 16 AN: 24566

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19536

East Asian (EAS) AF: 0.00 AC: 0 AN: 27382

South Asian (SAS) AF: 0.00 AC: 0 AN: 57436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3512

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1002800

Other (OTH) AF: 0.00 AC: 0 AN: 50048

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74426

African (AFR) AF: 0.000626 AC: 26 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.61
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.027
Sift	Benign	0.13	T
Sift4G	Benign	0.69	T
Polyphen		0.31	B
Vest4		0.20
MutPred		0.13		Gain of glycosylation at P79 (P = 0.0324)
MVP		0.24
MPC		0.52
ClinPred		0.12	T
GERP RS		1.8
PromoterAI		0.0026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.18
Mutation Taster		=94/6	polymorphism

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: rs1004412705; hg19: chr16-28834815;