14-70946994-A-T

Variant names:

• chr14-70946994-A-T
• rs145807664
• NM_014982.3:c.233A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014982.3(PCNX1):​c.233A>T​(p.Asn78Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. N78T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCNX1 NM_014982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

Genes affected

PCNX1 (HGNC:19740): (pecanex 1) This gene encodes an evolutionarily conserved transmembrane protein similar to the pecanex protein in Drosophila. The fly protein is a component of the Notch signaling pathway, which functions in several developmental processes. [provided by RefSeq, Jul 2016]

ENSG00000287643 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014982.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNX1	NM_014982.3	MANE Select	c.233A>T	p.Asn78Ile	missense	Exon 2 of 36	NP_055797.2	Q96RV3-1
	PCNX1	NM_001308160.2		c.233A>T	p.Asn78Ile	missense	Exon 2 of 34	NP_001295089.1	Q96RV3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNX1	ENST00000304743.7	TSL:1 MANE Select	c.233A>T	p.Asn78Ile	missense	Exon 2 of 36	ENSP00000304192.2	Q96RV3-1
	PCNX1	ENST00000439984.7	TSL:1	c.233A>T	p.Asn78Ile	missense	Exon 2 of 34	ENSP00000396617.3	Q96RV3-4
	PCNX1	ENST00000554879.5	TSL:1	n.679A>T		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461516 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111766

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.39
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.75		Loss of methylation at R80 (P = 0.0747)
MVP		0.068
MPC		0.41
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.64
gMVP		0.90
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145807664; hg19: chr14-71413711;