Genetic Variant PRSS56:p.Gln356ProfsTer152 (chr2-232523817-A-AC) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001195129.2(PRSS56):c.1066dupC(p.Gln356ProfsTer152) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,530,524 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

PRSS56
NM_001195129.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -1.82

Publications

15 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: G2P, Labcorp Genetics (formerly Invitae)
nanophthalmia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRSS56 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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-A-AC is Pathogenic according to our data. Variant chr2-232523817-A-AC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	NM_001195129.2	MANE Select	c.1066dupC	p.Gln356ProfsTer152	frameshift	Exon 9 of 13	NP_001182058.1	P0CW18
	PRSS56	NM_001369848.1		c.1069dupC	p.Gln357ProfsTer152	frameshift	Exon 9 of 13	NP_001356777.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	ENST00000617714.2	TSL:5 MANE Select	c.1066dupC	p.Gln356ProfsTer152	frameshift	Exon 9 of 13	ENSP00000479745.1	P0CW18

Frequencies

GnomAD3 genomes

AF:

0.000399

AC:

AN:

150424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000539

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000924

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.0000961

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000252

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000377

AC:

AN:

124514

AF XY:

0.000469

show subpopulations

Gnomad AFR exome

AF:

0.000359

Gnomad AMR exome

AF:

0.000209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000508

Gnomad FIN exome

AF:

0.000941

Gnomad NFE exome

AF:

0.000497

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000388

AC:

536

AN:

1379988

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

264

AN XY:

680812

show subpopulations

African (AFR)

AF:

0.000287

AC:

AN:

31400

American (AMR)

AF:

0.000225

AC:

AN:

35576

Ashkenazi Jewish (ASJ)

AF:

0.0000398

AC:

AN:

25108

East Asian (EAS)

AF:

0.000309

AC:

AN:

35554

South Asian (SAS)

AF:

0.000304

AC:

AN:

79058

European-Finnish (FIN)

AF:

0.000598

AC:

AN:

33450

Middle Eastern (MID)

AF:

0.000905

AC:

AN:

4422

European-Non Finnish (NFE)

AF:

0.000398

AC:

429

AN:

1077730

Other (OTH)

AF:

0.000520

AC:

AN:

57690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.000399

AC:

AN:

150536

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

AN XY:

73504

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

40902

American (AMR)

AF:

0.000923

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5054

South Asian (SAS)

AF:

0.00106

AC:

AN:

4726

European-Finnish (FIN)

AF:

0.0000961

AC:

AN:

10406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000252

AC:

AN:

67522

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000618

Hom.:

Bravo

AF:

0.000389

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Isolated microphthalmia 6 (5)

Nanophthalmia (1)

not provided (1)

PRSS56-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.8

Mutation Taster

=18/182

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 11

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

Publications

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2-232523817-AC-ACC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over