Genetic Variant PRSS56:p.Gly237Arg (chr2-232523062-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP3_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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

PRSS56
NM_001195129.2 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.31

Publications

1 publications found

Variant links:

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

PRSS56 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a domain Peptidase S1 (size 232) in uniprot entity PRS56_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001195129.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195129.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	NM_001195129.2	MANE Select	c.709G>C	p.Gly237Arg	missense splice_region	Exon 7 of 13	NP_001182058.1
	PRSS56	NM_001369848.1		c.709G>C	p.Gly237Arg	missense splice_region	Exon 7 of 13	NP_001356777.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	ENST00000617714.2	TSL:5 MANE Select	c.709G>C	p.Gly237Arg	missense splice_region	Exon 7 of 13	ENSP00000479745.1
	PRSS56	ENST00000602410.1	TSL:2	n.364G>C		splice_region non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000751

AC:

AN:

133128

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000192

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000723

AC:

AN:

1382278

Hom.:

Cov.:

AF XY:

0.00000587

AC XY:

AN XY:

681982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31548

American (AMR)

AF:

0.00

AC:

AN:

35494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35698

South Asian (SAS)

AF:

0.00

AC:

AN:

79038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00000928

AC:

AN:

1078074

Other (OTH)

AF:

0.00

AC:

AN:

57812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Benign

0.88

DEOGEN2

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.95

MutationAssessor

Benign

1.9

PhyloP100

5.3

PrimateAI

Pathogenic

0.83

Sift4G

Uncertain

0.010

Vest4

0.90

MVP

0.72

GERP RS

4.2

Varity_R

0.58

gMVP

0.88

Mutation Taster

=51/49

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over