14-39181720-A-T

Position:

• chr14-39181720-A-T

Variant summary

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

The NM_002687.4(PNN):​c.2011A>T​(p.Ser671Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S671G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNN NM_002687.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03

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]

ACMG classification

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	c.2011A>T	p.Ser671Cys	missense_variant	9/9	ENST00000216832.9	NP_002678.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNN	ENST00000216832.9	c.2011A>T	p.Ser671Cys	missense_variant	9/9	1	NM_002687.4	ENSP00000216832	P1
PNN	ENST00000557680.1	n.471-589A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.0043	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.27		Loss of phosphorylation at S671 (P = 3e-04);
MVP		0.51
MPC		0.067
ClinPred		0.80	D
GERP RS		4.7
Varity_R		0.43
gMVP		0.084

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

Other links and lift over

dbSNP: rs13021; hg19: chr14-39650924;