2-232525489-C-G

Position:

• chr2-232525489-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001195129.2(PRSS56):​c.1795C>G​(p.Pro599Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,495,064 control chromosomes in the GnomAD database, including 3,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (229 hom., cov: 33)
  • Exomes 𝑓: 0.061 (2781 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: -0.607

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016350746).
• BP6: Variant 2-232525489-C-G is Benign according to our data. Variant chr2-232525489-C-G is described in ClinVar as [Benign]. Clinvar id is 31078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232525489-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.1795C>G	p.Pro599Ala	missense_variant	13/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.1798C>G	p.Pro600Ala	missense_variant	13/13		NP_001356777.1
PRSS56	XM_047445431.1	c.1891C>G	p.Pro631Ala	missense_variant	12/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.1795C>G	p.Pro599Ala	missense_variant	13/13	5	NM_001195129.2	ENSP00000479745.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7026 AN: 152046 Hom.: 229 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0398

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0501 AC: 5310 AN: 105950 Hom.: 186 AF XY: 0.0520 AC XY: 3005 AN XY: 57796

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000206

Gnomad SAS exome AF: 0.0462

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0702

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0612 AC: 82165 AN: 1342900 Hom.: 2781 Cov.: 36 AF XY: 0.0612 AC XY: 40176 AN XY: 656442

Gnomad4 AFR exome AF: 0.00848

Gnomad4 AMR exome AF: 0.0322

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0000861

Gnomad4 SAS exome AF: 0.0477

Gnomad4 FIN exome AF: 0.0490

Gnomad4 NFE exome AF: 0.0658

Gnomad4 OTH exome AF: 0.0611

GnomAD4 genome AF: 0.0461 AC: 7022 AN: 152164 Hom.: 229 Cov.: 33 AF XY: 0.0449 AC XY: 3340 AN XY: 74378

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0398

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.0385

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0676

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0449 Hom.: 63

Bravo AF: 0.0436

TwinsUK AF: 0.0566 AC: 210

ALSPAC AF: 0.0602 AC: 232

ExAC AF: 0.0372 AC: 656

Asia WGS AF: 0.0180 AC: 65 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 6 Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 27884173, 21532570) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 51/2178=2.34% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.2
DANN	Benign	0.49
DEOGEN2	Benign	0.0083	T;T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0016	T;T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.57	T;T
Vest4		0.10
GERP RS		-4.5
Varity_R		0.022
gMVP		0.11

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: rs61744404; hg19: chr2-233390199;