rs730882160

chr2-232523062-G-Achr2-232523062-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.709G>A(p.Gly237Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000289 in 1,382,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PRSS56 NM_001195129.2 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.31

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 10 pathogenic changes around while only 1 benign (91%) in NM_001195129.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-232523062-G-A is Pathogenic according to our data. Variant chr2-232523062-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 183173.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS56	NM_001195129.2	c.709G>A	p.Gly237Arg	missense_variant, splice_region_variant	7/13	ENST00000617714.2
PRSS56	NM_001369848.1	c.709G>A	p.Gly237Arg	missense_variant, splice_region_variant	7/13
PRSS56	XM_047445431.1	c.709G>A	p.Gly237Arg	missense_variant, splice_region_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS56	ENST00000617714.2	c.709G>A	p.Gly237Arg	missense_variant, splice_region_variant	7/13	5	NM_001195129.2	P1
PRSS56	ENST00000602410.1	n.364G>A		splice_region_variant, non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1382278 Hom.: 0 Cov.: 34 AF XY: 0.00000147 AC XY: 1 AN XY: 681982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

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

Jan 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	36
Dann	Benign	0.90
DEOGEN2	Uncertain	0.57	D;D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.010	D;D
Vest4		0.90
MVP		0.72
GERP RS		4.2
Varity_R		0.58
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882160; hg19: chr2-233387772;