2-232524355-G-T

Variant names:

• chr2-232524355-G-T
• rs554826646
• NM_001195129.2:c.1400G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195129.2(PRSS56):​c.1400G>T​(p.Arg467Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,535,512 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (4 hom.)
• Consequence: PRSS56 NM_001195129.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 0.312
• Publications: 2 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=0.016842335).
• BP6: Variant 2-232524355-G-T is Benign according to our data. Variant chr2-232524355-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 191153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (186/152362) while in subpopulation AFR AF = 0.00392 (163/41600). AF 95% confidence interval is 0.00343. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.1400G>T	p.Arg467Leu	missense	Exon 11 of 13	NP_001182058.1	P0CW18
	PRSS56	NM_001369848.1		c.1403G>T	p.Arg468Leu	missense	Exon 11 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.1400G>T	p.Arg467Leu	missense	Exon 11 of 13	ENSP00000479745.1	P0CW18

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000378 AC: 50 AN: 132316 AF XY: 0.000319

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000194 AC: 269 AN: 1383150 Hom.: 4 Cov.: 36 AF XY: 0.000179 AC XY: 122 AN XY: 682460

African (AFR) AF: 0.00428 AC: 135 AN: 31574

American (AMR) AF: 0.000449 AC: 16 AN: 35662

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79156

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

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5652

European-Non Finnish (NFE) AF: 0.0000556 AC: 60 AN: 1078712

Other (OTH) AF: 0.000726 AC: 42 AN: 57870

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152362 Hom.: 0 Cov.: 34 AF XY: 0.00125 AC XY: 93 AN XY: 74508

African (AFR) AF: 0.00392 AC: 163 AN: 41600

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.00128

ExAC AF: 0.0000611 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.017	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.31
PrimateAI	Uncertain	0.54	T
Sift4G	Uncertain	0.0020	D
Vest4		0.24
MVP		0.59
GERP RS		2.2
Varity_R		0.34
gMVP		0.37
Mutation Taster		=96/4	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: rs554826646; hg19: chr2-233389065;