2-232520686-G-A

Position:

• chr2-232520686-G-A

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.88G>A​(p.Ala30Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,530,984 control chromosomes in the GnomAD database, including 371,791 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32965 hom., cov: 32)
  • Exomes 𝑓: 0.70 (338826 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.922

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=5.478455E-7).
• BP6: Variant 2-232520686-G-A is Benign according to our data. Variant chr2-232520686-G-A is described in ClinVar as [Benign]. Clinvar id is 677180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232520686-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.88G>A	p.Ala30Thr	missense_variant	1/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.88G>A	p.Ala30Thr	missense_variant	1/13		NP_001356777.1
PRSS56	XM_047445431.1	c.88G>A	p.Ala30Thr	missense_variant	1/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.88G>A	p.Ala30Thr	missense_variant	1/13	5	NM_001195129.2	ENSP00000479745	P1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98494 AN: 151898 Hom.: 32938 Cov.: 32

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.901

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.717 AC: 95950 AN: 133744 Hom.: 35002 AF XY: 0.714 AC XY: 51929 AN XY: 72780

Gnomad AFR exome AF: 0.470

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.899

Gnomad SAS exome AF: 0.685

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.695

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.699 AC: 963286 AN: 1378968 Hom.: 338826 Cov.: 33 AF XY: 0.699 AC XY: 475195 AN XY: 680082

Gnomad4 AFR exome AF: 0.472

Gnomad4 AMR exome AF: 0.775

Gnomad4 ASJ exome AF: 0.696

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.688

Gnomad4 FIN exome AF: 0.757

Gnomad4 NFE exome AF: 0.697

Gnomad4 OTH exome AF: 0.692

GnomAD4 genome AF: 0.648 AC: 98559 AN: 152016 Hom.: 32965 Cov.: 32 AF XY: 0.655 AC XY: 48679 AN XY: 74314

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.707

Gnomad4 ASJ AF: 0.687

Gnomad4 EAS AF: 0.901

Gnomad4 SAS AF: 0.698

Gnomad4 FIN AF: 0.763

Gnomad4 NFE AF: 0.694

Gnomad4 OTH AF: 0.626

Alfa AF: 0.688 Hom.: 24034

Bravo AF: 0.640

TwinsUK AF: 0.706 AC: 2616

ALSPAC AF: 0.708 AC: 2729

ExAC AF: 0.609 AC: 10624

Asia WGS AF: 0.754 AC: 2621 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.0041	T;T
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.18	T;T
MetaRNN	Benign	5.5e-7	T;T
MutationAssessor	Benign	-0.34	.;N
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	1.0	T;T
Vest4		0.029
GERP RS		2.3
Varity_R		0.039
gMVP		0.28

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: rs1550094; hg19: chr2-233385396; COSMIC: COSV71930103; COSMIC: COSV71930103;