17-78992383-C-T

Position:

• chr17-78992383-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001159773.2(CANT1):​c.*1167G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00986 in 282,022 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (15 hom.)
• Consequence: CANT1 NM_001159773.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.394

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00892 (1359/152270) while in subpopulation NFE AF= 0.0146 (994/68024). AF 95% confidence interval is 0.0139. There are 11 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CANT1	NM_001159773.2	c.*1167G>A		3_prime_UTR_variant	5/5	ENST00000392446.10
CANT1	NM_001159772.2	c.*1167G>A		3_prime_UTR_variant	6/6
CANT1	NM_138793.4	c.*1167G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CANT1	ENST00000392446.10	c.*1167G>A		3_prime_UTR_variant	5/5	1	NM_001159773.2	P1
CANT1	ENST00000302345.6	c.*1167G>A		3_prime_UTR_variant	4/4	2		P1
CANT1	ENST00000620915.4	c.*1167G>A		3_prime_UTR_variant	4/4	5		P1
CANT1	ENST00000592228.1	c.*204+27G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1358 AN: 152152 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0110 AC: 1422 AN: 129752 Hom.: 15 Cov.: 0 AF XY: 0.0105 AC XY: 673 AN XY: 64244

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0000735

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.00292

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.00962

GnomAD4 genome AF: 0.00892 AC: 1359 AN: 152270 Hom.: 11 Cov.: 32 AF XY: 0.00784 AC XY: 584 AN XY: 74446

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0110 Hom.: 1

Bravo AF: 0.00926

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desbuquois dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs186436891; hg19: chr17-76988465;