rs554826646

Variant names:

• chr2-232524355-G-A
• rs554826646
• 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. The variant received 0 ACMG points: 2P and 2B. PM2 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 benign.

• 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
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21801206).

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.1400G>A	p.Arg467His	missense	Exon 11 of 13	NP_001182058.1
	PRSS56	NM_001369848.1		c.1403G>A	p.Arg468His	missense	Exon 11 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.1400G>A	p.Arg467His	missense	Exon 11 of 13	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

African (AFR) AF: 0.00 AC: 0 AN: 31574

American (AMR) AF: 0.00 AC: 0 AN: 35662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078712

Other (OTH) AF: 0.00 AC: 0 AN: 57870

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.22	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.31
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.0020	D
Vest4		0.075
MVP		0.26
GERP RS		2.2
Varity_R		0.10
gMVP		0.27
Mutation Taster		=97/3	polymorphism

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: rs554826646; hg19: chr2-233389065;