rs587776895

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001159773.2(CANT1):c.902_906dupGCGCC(p.Ser303AlafsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,600,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A302A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CANT1
NM_001159773.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.35

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]

CANT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-78993849-T-TGGCGC is Pathogenic according to our data. Variant chr17-78993849-T-TGGCGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CANT1	NM_001159773.2 link	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift_variant	Exon 5 of 5	ENST00000392446.10	NP_001153245.1	Q8WVQ1-1A0A024R8U8
CANT1	NM_001159772.2 link	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift_variant	Exon 6 of 6		NP_001153244.1	Q8WVQ1-1A0A024R8U8
CANT1	NM_138793.4 link	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift_variant	Exon 4 of 4		NP_620148.1	Q8WVQ1-1A0A024R8U8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CANT1	ENST00000392446.10 link	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift_variant	Exon 5 of 5	1	NM_001159773.2	ENSP00000376241.4		Q8WVQ1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000846

AC:

AN:

236346

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000927

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1448598

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33352

Gnomad4 AMR exome

AF:

0.0000451

AC:

AN:

44394

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25940

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39518

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

85894

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

45852

Gnomad4 NFE exome

AF:

0.0000181

AC:

AN:

1107876

Gnomad4 Remaining exome

AF:

0.0000167

AC:

AN:

60022

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000196

AC:

0.000196232

AN:

0.000196232

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000146994

AN:

0.0000146994

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Desbuquois dysplasia 1

Pathogenic:5

Jan 30, 2022

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The homozygous frameshift insertion variant c.906_907insGCGCC (p.S303Afs*20) has been previously reported by Huber C et al in 2009 in a Moroccan patient. The allele frequency is 0.0008% in gnomAD (aggregated) database. In-silico bioinformatic software predict this variant by mutation taster as Disease causing. The phenotype observed was micromelia, monkey wrench feature. Desbuquois Dysplasia 1 is an autosomal recessive disorder. Based on the phenotypic observation, we classify this variant as pathogenic. -

May 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Centogene AG - the Rare Disease Company

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2021

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:4

May 21, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser303Alafs*21) in the CANT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the CANT1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Desbuquois dysplasia (PMID: 19853239, 28229453, 29620724). ClinVar contains an entry for this variant (Variation ID: 31013). For these reasons, this variant has been classified as Pathogenic. -

Jun 13, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation, as the last 99 amino acids are replaced with 20 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34853893, 34645488, 19853239, 31585110, 28229453, 20425819, 31130284, 32860008, 29620724, 34406647, 36331722) -

CANT1-related disorder

Pathogenic:1

Nov 06, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CANT1 c.902_906dup5 variant is predicted to result in a frameshift and premature protein termination (p.Ser303Alafs*21). This variant was reported in multiple individuals with autosomal recessive Desbuquois dysplasia (Huber. 2009. PubMed ID: 19853239; Al-Hamed. 2021. PubMed ID: 34853893; Table S6, Maddirevula. 2018. PubMed ID: 29620724; Ranza. 2017. PubMed ID: 28229453). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-76989931-T-TGGCGC). Frameshift variants in CANT1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=0/200

disease causing (ClinVar)

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over