chr2-232525249-G-C

Position:

• chr2-232525249-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PS1 PM2 BP4_Strong

The NM_001195129.2(PRSS56):​c.1555G>C​(p.Gly519Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000125 in 1,361,458 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (1 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19

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 Uncertain_significance. Variant got 2 ACMG points.

• PS1: Transcript NM_001195129.2 (PRSS56) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013643622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.1555G>C	p.Gly519Arg	missense_variant	13/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.1558G>C	p.Gly520Arg	missense_variant	13/13		NP_001356777.1
PRSS56	XM_047445431.1	c.1651G>C	p.Gly551Arg	missense_variant	12/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.1555G>C	p.Gly519Arg	missense_variant	13/13	5	NM_001195129.2	ENSP00000479745.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000262 AC: 3 AN: 114572 Hom.: 1 AF XY: 0.0000480 AC XY: 3 AN XY: 62556

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 SAS exome AF: 0.000152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 17 AN: 1361458 Hom.: 1 Cov.: 36 AF XY: 0.0000149 AC XY: 10 AN XY: 669058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000196

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000518 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Benign	0.90
DEOGEN2	Benign	0.068	T;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.014	T;T
MutationAssessor	Benign	0.97	.;L
PrimateAI	Uncertain	0.76	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.84
MVP		0.70
GERP RS		3.2
Varity_R		0.088
gMVP		0.85

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: rs730882162; hg19: chr2-233389959;