rs387907095

Positions:

• chr2-232523492-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001195129.2(PRSS56):​c.926G>C​(p.Trp309Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,378,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 9/14 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.64

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity PRS56_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001195129.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 2-232523492-G-C is Pathogenic according to our data. Variant chr2-232523492-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 31079.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.926G>C	p.Trp309Ser	missense_variant	8/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.926G>C	p.Trp309Ser	missense_variant	8/13		NP_001356777.1
PRSS56	XM_047445431.1	c.926G>C	p.Trp309Ser	missense_variant	8/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.926G>C	p.Trp309Ser	missense_variant	8/13	5	NM_001195129.2	ENSP00000479745.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1378004 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 679578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.29e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Isolated microphthalmia 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 11, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Benign	0.87
DEOGEN2	Uncertain	0.58	D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.93	D;D
MutationAssessor	Pathogenic	2.9	.;M
PrimateAI	Pathogenic	0.85	D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.85
MVP		0.75
GERP RS		4.1
Varity_R		0.89
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs387907095; hg19: chr2-233388202;