rs730882160

Variant names:

• chr2-232523062-G-A
• rs730882160
• NM_001195129.2:c.709G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232523062-G-A
• chr2-232523062-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001195129.2(PRSS56):​c.709G>A​(p.Gly237Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000289 in 1,382,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PRSS56 NM_001195129.2 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.31
• 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: G2P, Labcorp Genetics (formerly Invitae)
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity PRS56_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001195129.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-232523062-G-A is Pathogenic according to our data. Variant chr2-232523062-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 183173.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	NM_001195129.2	MANE Select	c.709G>A	p.Gly237Arg	missense splice_region	Exon 7 of 13	NP_001182058.1	P0CW18
	PRSS56	NM_001369848.1		c.709G>A	p.Gly237Arg	missense splice_region	Exon 7 of 13	NP_001356777.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	ENST00000617714.2	TSL:5 MANE Select	c.709G>A	p.Gly237Arg	missense splice_region	Exon 7 of 13	ENSP00000479745.1	P0CW18
	PRSS56	ENST00000602410.1	TSL:2	n.364G>A		splice_region non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1382278 Hom.: 0 Cov.: 34 AF XY: 0.00000147 AC XY: 1 AN XY: 681982

African (AFR) AF: 0.00 AC: 0 AN: 31548

American (AMR) AF: 0.00 AC: 0 AN: 35494

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 35698

South Asian (SAS) AF: 0.00 AC: 0 AN: 79038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078074

Other (OTH) AF: 0.00 AC: 0 AN: 57812

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

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	0.77
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Benign	0.90
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.3
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.010	D
Vest4		0.90
MVP		0.72
GERP RS		4.2
Varity_R		0.58
gMVP		0.88
Mutation Taster		=49/51	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882160; hg19: chr2-233387772;