rs730882064

Variant names:

• chr2-232523817-AC-A
• rs730882064
• NM_001195129.2:c.1066delC

Your query was ambiguous. Multiple possible variants found:

• chr2-232523817-AC-A
• chr2-232523817-AC-ACC
• chr2-232523817-AC-ACCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001195129.2(PRSS56):​c.1066delC​(p.Gln356ArgfsTer148) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 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 rank	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.1066delC	p.Gln356ArgfsTer148	frameshift_variant	Exon 9 of 13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.1069delC	p.Gln357ArgfsTer148	frameshift_variant	Exon 9 of 13		NP_001356777.1
PRSS56	XM_047445431.1	c.1069delC	p.Gln357ArgfsTer61	frameshift_variant	Exon 9 of 12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.1066delC	p.Gln356ArgfsTer148	frameshift_variant	Exon 9 of 13	5	NM_001195129.2	ENSP00000479745.1

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150426 Hom.: 0 Cov.: 34

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: 35 AN: 1379944 Hom.: 0 Cov.: 35 AF XY: 0.0000294 AC XY: 20 AN XY: 680776

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: 6 AN: 150538 Hom.: 0 Cov.: 34 AF XY: 0.0000408 AC XY: 3 AN XY: 73506

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

Submissions by phenotype

Isolated microphthalmia 6 Pathogenic:1

Nov 14, 2022

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.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. 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. 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). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs730882064; hg19: chr2-233388527;