2-232520611-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001195129.2(PRSS56):c.13G>A(p.Val5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,536,042 control chromosomes in the GnomAD database, including 19 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 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (16 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.860

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020445883).
• BP6: Variant 2-232520611-G-A is Benign according to our data. Variant chr2-232520611-G-A is described in ClinVar as [Benign]. Clinvar id is 2777777.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-232520611-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00116 (176/152290) while in subpopulation EAS AF= 0.0334 (173/5180). AF 95% confidence interval is 0.0293. There are 3 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS56	NM_001195129.2	c.13G>A	p.Val5Met	missense_variant	1/13	ENST00000617714.2
PRSS56	NM_001369848.1	c.13G>A	p.Val5Met	missense_variant	1/13
PRSS56	XM_047445431.1	c.13G>A	p.Val5Met	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS56	ENST00000617714.2	c.13G>A	p.Val5Met	missense_variant	1/13	5	NM_001195129.2	P1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152172 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00297 AC: 400 AN: 134638 Hom.: 5 AF XY: 0.00281 AC XY: 206 AN XY: 73298

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0361

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.000848 AC: 1173 AN: 1383752 Hom.: 16 Cov.: 31 AF XY: 0.000822 AC XY: 561 AN XY: 682836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0294

Gnomad4 SAS exome AF: 0.000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000465 AC: 12

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Benign	0.86
DEOGEN2	Benign	0.014	T;T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0020	T;T
PrimateAI	Uncertain	0.49	T
Sift4G	Uncertain	0.012	D;D
Vest4		0.13
MVP		0.24
GERP RS		-7.4
Varity_R		0.025
gMVP		0.32

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: rs2697778; hg19: chr2-233385321;