rs554826646

Variant names:

• chr2-232524355-G-A
• NM_001195129.2:c.1400G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232524355-G-A
• chr2-232524355-G-C
• chr2-232524355-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001195129.2(PRSS56):​c.1400G>A​(p.Arg467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.312

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-232524355-G-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21801206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS56	NM_001195129.2	c.1400G>A	p.Arg467His	missense_variant	Exon 11 of 13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.1403G>A	p.Arg468His	missense_variant	Exon 11 of 13		NP_001356777.1
PRSS56	XM_047445431.1	c.1496G>A	p.Arg499His	missense_variant	Exon 10 of 12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2	c.1400G>A	p.Arg467His	missense_variant	Exon 11 of 13	5	NM_001195129.2	ENSP00000479745.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383150 Hom.: 0 Cov.: 36 AF XY: 0.00000147 AC XY: 1 AN XY: 682460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 6 Uncertain:1

Sep 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 467 of the PRSS56 protein (p.Arg467His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PRSS56-related conditions (PMID: 25587058). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.013	T;T
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.62	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.22	T;T
MutationAssessor	Benign	0.90	.;L
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.0020	D;D
Vest4		0.075
MVP		0.26
GERP RS		2.2
Varity_R		0.10
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233389065;