rs61744404

Variant names:

• chr2-232525489-C-G
• rs61744404
• NM_001195129.2:c.1795C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-232525489-C-G
• chr2-232525489-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001195129.2(PRSS56):​c.1795C>G​(p.Pro599Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,495,064 control chromosomes in the GnomAD database, including 3,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P599P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (229 hom., cov: 33)
  • Exomes 𝑓: 0.061 (2781 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: -0.607
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016350746).
• BP6: Variant 2-232525489-C-G is Benign according to our data. Variant chr2-232525489-C-G is described in ClinVar as Benign. ClinVar VariationId is 31078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

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.1795C>G	p.Pro599Ala	missense	Exon 13 of 13	NP_001182058.1	P0CW18
	PRSS56	NM_001369848.1		c.1798C>G	p.Pro600Ala	missense	Exon 13 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.1795C>G	p.Pro599Ala	missense	Exon 13 of 13	ENSP00000479745.1	P0CW18

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7026 AN: 152046 Hom.: 229 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0398

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0501 AC: 5310 AN: 105950 AF XY: 0.0520

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000206

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0702

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0612 AC: 82165 AN: 1342900 Hom.: 2781 Cov.: 36 AF XY: 0.0612 AC XY: 40176 AN XY: 656442

African (AFR) AF: 0.00848 AC: 259 AN: 30540

American (AMR) AF: 0.0322 AC: 1051 AN: 32658

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2570 AN: 23384

East Asian (EAS) AF: 0.0000861 AC: 3 AN: 34850

South Asian (SAS) AF: 0.0477 AC: 3593 AN: 75276

European-Finnish (FIN) AF: 0.0490 AC: 1591 AN: 32468

Middle Eastern (MID) AF: 0.0782 AC: 377 AN: 4822

European-Non Finnish (NFE) AF: 0.0658 AC: 69308 AN: 1053006

Other (OTH) AF: 0.0611 AC: 3413 AN: 55896

GnomAD4 genome AF: 0.0461 AC: 7022 AN: 152164 Hom.: 229 Cov.: 33 AF XY: 0.0449 AC XY: 3340 AN XY: 74378

African (AFR) AF: 0.0114 AC: 475 AN: 41536

American (AMR) AF: 0.0398 AC: 608 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5136

South Asian (SAS) AF: 0.0385 AC: 186 AN: 4826

European-Finnish (FIN) AF: 0.0565 AC: 600 AN: 10626

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0676 AC: 4595 AN: 67956

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0449 Hom.: 63

Bravo AF: 0.0436

TwinsUK AF: 0.0566 AC: 210

ALSPAC AF: 0.0602 AC: 232

ExAC AF: 0.0372 AC: 656

Asia WGS AF: 0.0180 AC: 65 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	2	Isolated microphthalmia 6 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.2
DANN	Benign	0.49
DEOGEN2	Benign	0.0083	T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0016	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.61
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.57	T
Vest4		0.10
GERP RS		-4.5
Varity_R		0.022
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs61744404; hg19: chr2-233390199; COSMIC: COSV107251028;