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. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

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
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• isolated microphthalmia 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes AF: 0.0000562 AC: 7 AN: 124514 AF XY: 0.0000879

Gnomad AFR exome AF: 0.000179

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000127

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome 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

African (AFR) AF: 0.0000637 AC: 2 AN: 31394

American (AMR) AF: 0.00 AC: 0 AN: 35570

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25102

East Asian (EAS) AF: 0.0000563 AC: 2 AN: 35550

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4424

European-Non Finnish (NFE) AF: 0.0000260 AC: 28 AN: 1077708

Other (OTH) AF: 0.0000173 AC: 1 AN: 57686

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150538 Hom.: 0 Cov.: 34 AF XY: 0.0000408 AC XY: 3 AN XY: 73506

African (AFR) AF: 0.0000489 AC: 2 AN: 40902

American (AMR) AF: 0.0000659 AC: 1 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67522

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.00 Hom.: 0

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
Mutation Taster		=38/162	disease causing

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

Other links and lift over

dbSNP: rs730882064; hg19: chr2-233388527; COSMIC: COSV51317785; COSMIC: COSV51317785;