rs730882161

Variant names:

• chr2-232523942-T-C
• rs730882161
• NM_001195129.2:c.1183T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001195129.2(PRSS56):​c.1183T>C​(p.Cys395Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000738 in 1,355,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.98
• Publications: 1 publications found

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]

PRSS56 Gene-Disease associations (from GenCC):

• isolated microphthalmia 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 2-232523942-T-C is Pathogenic according to our data. Variant chr2-232523942-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 183174.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195129.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	NM_001195129.2	MANE Select	c.1183T>C	p.Cys395Arg	missense	Exon 9 of 13	NP_001182058.1
	PRSS56	NM_001369848.1		c.1186T>C	p.Cys396Arg	missense	Exon 9 of 13	NP_001356777.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	ENST00000617714.2	TSL:5 MANE Select	c.1183T>C	p.Cys395Arg	missense	Exon 9 of 13	ENSP00000479745.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000948 AC: 1 AN: 105456 AF XY: 0.0000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000487

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355256 Hom.: 0 Cov.: 35 AF XY: 0.00000150 AC XY: 1 AN XY: 666296

African (AFR) AF: 0.00 AC: 0 AN: 29800

American (AMR) AF: 0.0000314 AC: 1 AN: 31800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23448

East Asian (EAS) AF: 0.00 AC: 0 AN: 34720

South Asian (SAS) AF: 0.00 AC: 0 AN: 75272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065866

Other (OTH) AF: 0.00 AC: 0 AN: 56432

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Isolated microphthalmia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.92	D
MutationAssessor	Benign	0.97	L
PhyloP100		5.0
PrimateAI	Pathogenic	0.95	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MVP		0.70
GERP RS		3.9
Varity_R		0.84
gMVP		0.91
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882161; hg19: chr2-233388652;