Genetic Variant PRR18:p.Asp196Asn (chr6-166307557-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_175922.4(PRR18):c.586G>A(p.Asp196Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 149,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRR18
NM_175922.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0870

Variant links:

Genes affected

PRR18 (HGNC:28574): (proline rich 18)

PRR18 links:

LOC107986669 (HGNC:):

LOC107986669 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043248326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4 link	c.586G>A	p.Asp196Asn	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2	Q8N4B5
LOC107986669	XR_001744464.2 link	n.10C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5 link	c.586G>A	p.Asp196Asn	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3		Q8N4B5
PRR18	ENST00000529616.1 link	c.*236G>A		downstream_gene_variant		2		ENSP00000433381.1		E9PL31

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149560

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1061438

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

501854

African (AFR)

AF:

0.00

AC:

AN:

21942

American (AMR)

AF:

0.00

AC:

AN:

7628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13162

East Asian (EAS)

AF:

0.00

AC:

AN:

24728

South Asian (SAS)

AF:

0.00

AC:

AN:

20164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2868

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

907848

Other (OTH)

AF:

0.00

AC:

AN:

42024

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72956

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41022

American (AMR)

AF:

0.00

AC:

AN:

15030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000198

AC:

AN:

5042

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67214

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.586G>A (p.D196N) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a G to A substitution at nucleotide position 586, causing the aspartic acid (D) at amino acid position 196 to be replaced by an asparagine (N). 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

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0078

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.34

M_CAP

Benign

0.077

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.087

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.34

REVEL

Benign

0.017

Sift

Benign

0.83

Sift4G

Benign

0.62

Polyphen

0.021

Vest4

0.062

MutPred

0.12

Gain of glycosylation at P198 (P = 0.1018);

MVP

0.014

MPC

1.8

ClinPred

0.11

GERP RS

2.0

Varity_R

0.029

gMVP

0.092

Mutation Taster

=97/3

polymorphism

(source)

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

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6-166307557-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over