2-232523817-AC-ACC

Position:

• chr2-232523817-AC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001195129.2(PRSS56):​c.1066dupC​(p.Gln356fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,530,524 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: PRSS56 NM_001195129.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -1.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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-A-AC is Pathogenic according to our data. Variant chr2-232523817-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.1066dupC	p.Gln356fs	frameshift_variant	9/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.1069dupC	p.Gln357fs	frameshift_variant	9/13		NP_001356777.1
PRSS56	XM_047445431.1	c.1069dupC	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	c.1066dupC	p.Gln356fs	frameshift_variant	9/13	5	NM_001195129.2	ENSP00000479745.1

Frequencies

GnomAD3 genomes AF: 0.000399 AC: 60 AN: 150424 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000924

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 0.000388 AC: 536 AN: 1379988 Hom.: 1 Cov.: 35 AF XY: 0.000388 AC XY: 264 AN XY: 680812

Gnomad4 AFR exome AF: 0.000287

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.000309

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.000598

Gnomad4 NFE exome AF: 0.000398

Gnomad4 OTH exome AF: 0.000520

GnomAD4 genome AF: 0.000399 AC: 60 AN: 150536 Hom.: 0 Cov.: 34 AF XY: 0.000408 AC XY: 30 AN XY: 73504

Gnomad4 AFR AF: 0.000538

Gnomad4 AMR AF: 0.000923

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.0000961

Gnomad4 NFE AF: 0.000252

Gnomad4 OTH AF: 0.000477

Bravo AF: 0.000389

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 6 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2021	This sequence change creates a premature translational stop signal (p.Gln356Profs*152) in the PRSS56 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRSS56 are known to be pathogenic (PMID: 31266062, 31992737). This variant is present in population databases (rs746758123, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with posterior microphthalmia (PMID: 21397065, 21532570, 23127749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31077). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000031077, PMID:21397065). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000367, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

PRSS56-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2023

The PRSS56 c.1066dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln356Profs*152). This variant has been reported as pathogenic for autosomal recessive microphthalmia (Gal et al. 2011. PubMed ID: 21397065; Prasov et al. 2020. PubMed ID: 33203948). This variant is reported in 0.069% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-233388527-A-AC) and is classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/31077). This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2019

Considered a founder mutation in the Tunisian population (Nair et al., 2011); Observed in homozygous state in multiple unrelated patients in published literature (Nowilaty et al., 2013) and not observed in homozygous state in controls; Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 248 amino acids are lost and replaced with 151 incorrect amino acids; Observed in 0.0324% (10/30878 alleles) in large population cohorts (Lek et al., 2016) -

Nanophthalmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 08, 2019

The p.Gln356ProfsX152 variant in PRSS56 has been reported as a homozygous variant in 7 consanguineous families with posterior microphthalmos, and as a heterozygous variant in 2 individuals with primary angle-closure glaucoma (PACG) and high hyperopia (Aldahmesh 2011, Nair 2011, Gal 2011, Nowilaty 2013, Jiang 2013). In the 7 consanguineous families, this variant segregated in the homozygous state in at least 12 additional affected relatives, and no tested unaffected relatives were homozygous (Nair 2011, Gal 2011). This variant has also been identified in 0.06% (6/8736) of Finish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 356 and leads to a premature termination codon 152 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive posterior microphthalmos. ACMG/AMP Criteria applied: PP1_Strong; PM3. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 11

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882064; hg19: chr2-233388527;