chr17-78993849-T-TGGCGC

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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Desbuquois dysplasia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Desbuquois dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 4 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 31013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159773.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CANT1	NM_001159773.2	MANE Select	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift	Exon 5 of 5	NP_001153245.1
CANT1	NM_001159772.2		c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift	Exon 6 of 6	NP_001153244.1
CANT1	NM_138793.4		c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift	Exon 4 of 4	NP_620148.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CANT1	ENST00000392446.10	TSL:1 MANE Select	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift	Exon 5 of 5	ENSP00000376241.4
CANT1	ENST00000591773.5	TSL:1	c.902_906dupGCGCC	p.Ser303AlafsTer21	frameshift	Exon 6 of 6	ENSP00000467437.1
CANT1	ENST00000588096.1	TSL:1	n.299_303dupGCGCC		non_coding_transcript_exon	Exon 2 of 2

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

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.0000451

AC:

AN:

44394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.00

AC:

AN:

85894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1107876

Other (OTH)

AF:

0.0000167

AC:

AN:

60022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.613

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

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

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.

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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

Nov 30, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 21, 2018

Eurofins Ntd Llc (ga)

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over