22-45672142-C-T

Variant names:

• chr22-45672142-C-T
• NM_013236.4:c.79C>T

Variant summary

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

The NM_013236.4(ATXN10):​c.79C>T​(p.Arg27Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ATXN10 NM_013236.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.258

Genes affected

ATXN10 (HGNC:10549): (ataxin 10) This gene encodes a protein that may function in neuron survival, neuron differentiation, and neuritogenesis. These roles may be carried out via activation of the mitogen-activated protein kinase cascade. Expansion of an ATTCT repeat from 9-32 copies to 800-4500 copies in an intronic region of this locus has been associated with spinocerebellar ataxia, type 10. Alternatively spliced transcript variants have been described.[provided by RefSeq, Jul 2016]

ENSG00000280383 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN10	NM_013236.4	c.79C>T	p.Arg27Cys	missense_variant	Exon 1 of 12	ENST00000252934.10	NP_037368.1
ATXN10	NM_001167621.2	c.79C>T	p.Arg27Cys	missense_variant	Exon 1 of 11		NP_001161093.1
ATXN10	XM_047441314.1	c.79C>T	p.Arg27Cys	missense_variant	Exon 1 of 12		XP_047297270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN10	ENST00000252934.10	c.79C>T	p.Arg27Cys	missense_variant	Exon 1 of 12	1	NM_013236.4	ENSP00000252934.4
ATXN10	ENST00000381061.8	c.79C>T	p.Arg27Cys	missense_variant	Exon 1 of 11	2		ENSP00000370449.4
ENSG00000280383	ENST00000623075.1	n.15124C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ATXN10	ENST00000498009.5	n.-46C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387598 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 684712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79C>T (p.R27C) alteration is located in exon 1 (coding exon 1) of the ATXN10 gene. This alteration results from a C to T substitution at nucleotide position 79, causing the arginine (R) at amino acid position 27 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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;.
Eigen	Benign	0.022
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.042	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	L;L;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.29	N;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.026	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.30
MutPred		0.67		Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);
MVP		0.52
MPC		0.27
ClinPred		0.67	D
GERP RS		0.60
Varity_R		0.21
gMVP		0.28

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: chr22-46068022;