Variant chr2-232523817-AC-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001195129.2(PRSS56):c.1066delC(p.Gln356fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,530,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PRSS56
NM_001195129.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -1.82

Variant links:

Genes affected

PRSS56 (HGNC:39433): (serine protease 56) This gene encodes a protein that contains a peptidase S1 domain and possesses trypsin-like serine protease activity. The encoded protein may play a role in eye development, and mutations in this gene are a cause of autosomal recessive posterior microphthalmos. [provided by RefSeq, Dec 2011]

PRSS56 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-232523817-AC-A is Pathogenic according to our data. Variant chr2-232523817-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 1324965.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-232523817-AC-A is described in Lovd as [Pathogenic]. Variant chr2-232523817-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2 linkuse as main transcript	c.1066delC	p.Gln356fs	frameshift_variant	9/13	ENST00000617714.2	NP_001182058.1	P0CW18
PRSS56	NM_001369848.1 linkuse as main transcript	c.1069delC	p.Gln357fs	frameshift_variant	9/13		NP_001356777.1
PRSS56	XM_047445431.1 linkuse as main transcript	c.1069delC	p.Gln357fs	frameshift_variant	9/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2 linkuse as main transcript	c.1066delC	p.Gln356fs	frameshift_variant	9/13	5	NM_001195129.2	ENSP00000479745.1		P0CW18

Frequencies

GnomAD3 genomes

AF:

0.0000399

AC:

AN:

150426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

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:

0.0000444

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000254

AC:

AN:

1379944

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

680776

show subpopulations

Gnomad4 AFR exome

AF:

0.0000637

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000398

Gnomad4 EAS exome

AF:

0.0000563

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000260

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000399

AC:

AN:

150538

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73506

show subpopulations

Gnomad4 AFR

AF:

0.0000489

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000444

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Isolated microphthalmia 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2022

This sequence change creates a premature translational stop signal (p.Gln356Argfs*148) in the PRSS56 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 248 amino acid(s) of the PRSS56 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRSS56 protein in which other variant(s) (p.Arg563Alafs*17) have been determined to be pathogenic (PMID: 31266062; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1324965). This premature translational stop signal has been observed in individual(s) with nanophthalmia (PMID: 33203948). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

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