14-39179228-A-C

Position:

• chr14-39179228-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002687.4(PNN):​c.636A>C​(p.Lys212Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNN NM_002687.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNN	NM_002687.4	c.636A>C	p.Lys212Asn	missense_variant	7/9	ENST00000216832.9	NP_002678.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNN	ENST00000216832.9	c.636A>C	p.Lys212Asn	missense_variant	7/9	1	NM_002687.4	ENSP00000216832.4
PNN	ENST00000553331.5	c.*166A>C		3_prime_UTR_variant	6/6	3		ENSP00000452217.1
PNN	ENST00000554902.5	n.227A>C		non_coding_transcript_exon_variant	1/3	2
PNN	ENST00000557680.1	n.139A>C		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.636A>C (p.K212N) alteration is located in exon 7 (coding exon 7) of the PNN gene. This alteration results from a A to C substitution at nucleotide position 636, causing the lysine (K) at amino acid position 212 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	Pathogenic	1.0
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.18
Sift	Benign	0.045	D
Sift4G	Benign	0.10	T
Polyphen		0.92	P
Vest4		0.82
MutPred		0.65		Loss of ubiquitination at K212 (P = 0.0081);
MVP		0.64
MPC		2.1
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.68
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-39648432;