rs267606701

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001159773.2(CANT1):​c.898C>T​(p.Arg300Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,597,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R300H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CANT1
NM_001159773.2 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
CANT1 (HGNC:19721): (calcium activated nucleotidase 1) This protein encoded by this gene belongs to the apyrase family. It functions as a calcium-dependent nucleotidase with a preference for UDP. Mutations in this gene are associated with Desbuquois dysplasia with hand anomalies. Alternatively spliced transcript variants have been noted for this gene.[provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a strand (size 5) in uniprot entity CANT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001159773.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-78993857-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 17-78993858-G-A is Pathogenic according to our data. Variant chr17-78993858-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CANT1NM_001159773.2 linkuse as main transcriptc.898C>T p.Arg300Cys missense_variant 5/5 ENST00000392446.10
CANT1NM_001159772.2 linkuse as main transcriptc.898C>T p.Arg300Cys missense_variant 6/6
CANT1NM_138793.4 linkuse as main transcriptc.898C>T p.Arg300Cys missense_variant 4/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CANT1ENST00000392446.10 linkuse as main transcriptc.898C>T p.Arg300Cys missense_variant 5/51 NM_001159773.2 P1Q8WVQ1-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
GnomAD3 exomes
AF:
0.0000175
AC:
4
AN:
229118
Hom.:
0
AF XY:
0.0000318
AC XY:
4
AN XY:
125794
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000570
Gnomad SAS exome
AF:
0.0000337
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000192
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000138
AC:
20
AN:
1445590
Hom.:
0
Cov.:
31
AF XY:
0.0000209
AC XY:
15
AN XY:
718438
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000254
Gnomad4 SAS exome
AF:
0.0000584
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000469
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Desbuquois dysplasia 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2009- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 14, 2017- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeNov 29, 2022This missense change has been observed in individuals with Desbuquois dysplasia (PMID: 19853239). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CANT1 protein function. ClinVar contains an entry for this variant (Variation ID: 279). This variant is present in population databases (rs267606701, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 300 of the CANT1 protein (p.Arg300Cys). Experimental studies have shown that this missense change affects CANT1 function (PMID: 19853239, 21037275). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg300 amino acid residue in CANT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19853239, 22539336). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;D;D;D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
D;.;.;.
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H;H;H;H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.5
.;D;D;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.84
MutPred
0.98
Gain of catalytic residue at P299 (P = 0.0118);Gain of catalytic residue at P299 (P = 0.0118);Gain of catalytic residue at P299 (P = 0.0118);Gain of catalytic residue at P299 (P = 0.0118);
MVP
1.0
MPC
1.3
ClinPred
1.0
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.94
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606701; hg19: chr17-76989940; COSMIC: COSV104589621; COSMIC: COSV104589621; API