Variant 12-11392950-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006248.4(PRB2):c.1128T>G(p.Asn376Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,603,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000091 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

PRB2
NM_006248.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.76

Variant links:

Genes affected

PRB2 (HGNC:9338): (proline rich protein BstNI subfamily 2) This gene encodes a member of the heterogeneous family of basic, proline-rich, human salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature isoforms before secretion from the parotid glands. Multiple alleles of this gene exhibiting variations in the length of the tandem repeats, polymorphic cleavage sites and polymorphic stop codons have been identified. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. [provided by RefSeq, May 2023]

PRB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031402767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRB2	NM_006248.4 linkuse as main transcript	c.1128T>G	p.Asn376Lys	missense_variant	3/4	ENST00000389362.6	NP_006239.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRB2	ENST00000389362.6 linkuse as main transcript	c.1128T>G	p.Asn376Lys	missense_variant	3/4	5	NM_006248.4	ENSP00000374013	P1

Frequencies

GnomAD3 genomes

AF:

0.0000911

AC:

AN:

142662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000416

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000217

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000307

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000882

AC:

AN:

249360

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000436

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1460946

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.0000910

AC:

AN:

142784

Hom.:

Cov.:

AF XY:

0.0000431

AC XY:

AN XY:

69582

show subpopulations

Gnomad4 AFR

AF:

0.000105

Gnomad4 AMR

AF:

0.000416

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000217

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000307

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

ExAC

AF:

0.0000742

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The c.1128T>G (p.N376K) alteration is located in exon 3 (coding exon 3) of the PRB2 gene. This alteration results from a T to G substitution at nucleotide position 1128, causing the asparagine (N) at amino acid position 376 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0010

DANN

Benign

0.22

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.00095

M_CAP

Benign

0.0014

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

0.16

REVEL

Benign

0.0040

Sift4G

Benign

0.35

Vest4

0.088

MutPred

0.40

Gain of catalytic residue at P381 (P = 4e-04);

MVP

0.014

MPC

0.075

ClinPred

0.025

GERP RS

-2.8

gMVP

0.016

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over