Variant 14-39176558-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002687.4(PNN):c.217C>T(p.Pro73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,608,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PNN
NM_002687.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

Variant links:

Genes affected

PNN (HGNC:9162): (pinin, desmosome associated protein) Enables RNA binding activity. Predicted to be involved in cell adhesion and mRNA splicing, via spliceosome. Predicted to act upstream of or within cell-cell adhesion. Located in nuclear speck. Part of catalytic step 2 spliceosome. Colocalizes with exon-exon junction complex. [provided by Alliance of Genome Resources, Apr 2022]

PNN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNN	NM_002687.4 link	c.217C>T	p.Pro73Ser	missense_variant	3/9	ENST00000216832.9	NP_002678.3	Q9H307

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PNN	ENST00000216832.9 link	c.217C>T	p.Pro73Ser	missense_variant	3/9	1	NM_002687.4	ENSP00000216832.4	Q9H307
PNN	ENST00000553331.5 link	c.217C>T	p.Pro73Ser	missense_variant	3/6	3		ENSP00000452217.1	G3V579
PNN	ENST00000556530.1 link	c.217C>T	p.Pro73Ser	missense_variant	3/4	2		ENSP00000452318.1	G3V5F0
PNN	ENST00000554117.1 link	n.592C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246210

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133122

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1456480

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000780

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Nov 09, 2024

The c.217C>T (p.P73S) alteration is located in exon 3 (coding exon 3) of the PNN gene. This alteration results from a C to T substitution at nucleotide position 217, causing the proline (P) at amino acid position 73 to be replaced by a serine (S). 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

Pathogenic

0.91

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

.;D;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.97

.;L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.52

MVP

0.66

MPC

1.9

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.40

gMVP

0.44

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