2-232523062-G-C

Position:

• chr2-232523062-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001195129.2(PRSS56):​c.709G>C​(p.Gly237Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000723 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 predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: PRSS56 NM_001195129.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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]

PRSS56 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.709G>C	p.Gly237Arg	missense_variant, splice_region_variant	7/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.709G>C	p.Gly237Arg	missense_variant, splice_region_variant	7/13		NP_001356777.1
PRSS56	XM_047445431.1	c.709G>C	p.Gly237Arg	missense_variant, splice_region_variant	7/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.709G>C	p.Gly237Arg	missense_variant, splice_region_variant	7/13	5	NM_001195129.2	ENSP00000479745.1
PRSS56	ENST00000602410.1	n.364G>C		splice_region_variant, non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000751 AC: 1 AN: 133128 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000723 AC: 10 AN: 1382278 Hom.: 0 Cov.: 34 AF XY: 0.00000587 AC XY: 4 AN XY: 681982

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: 0.00000928

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Benign	0.88
DEOGEN2	Uncertain	0.57	D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.95	D;D
MutationAssessor	Benign	1.9	.;L
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)		0.0		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: rs730882160; hg19: chr2-233387772;