Genetic Variant NM_014982.3:c.1373C>T (chr14-70977710-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_014982.3(PCNX1):c.1373C>T(p.Ala458Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000875 in 1,614,036 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00091 ( 1 hom. )

Consequence

PCNX1
NM_014982.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.332

Variant links:

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]

PCNX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0036266744).

BP6

Variant 14-70977710-C-T is Benign according to our data. Variant chr14-70977710-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2285840.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNX1	NM_014982.3 link	c.1373C>T	p.Ala458Val	missense_variant	Exon 6 of 36	ENST00000304743.7	NP_055797.2	Q96RV3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCNX1	ENST00000304743.7 link	c.1373C>T	p.Ala458Val	missense_variant	Exon 6 of 36	1	NM_014982.3	ENSP00000304192.2	Q96RV3-1
PCNX1	ENST00000439984.7 link	c.1373C>T	p.Ala458Val	missense_variant	Exon 6 of 34	1		ENSP00000396617.3	Q96RV3-4
PCNX1	ENST00000554879.5 link	n.1819C>T		non_coding_transcript_exon_variant	Exon 6 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.00103

AC:

258

AN:

251344

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000907

AC:

1326

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000905

AC XY:

658

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00236

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000572

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.000864

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00124

AC:

151

EpiCase

AF:

0.000927

EpiControl

AF:

0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 27, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.083

DANN

Benign

0.63

DEOGEN2

Benign

0.012

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.0090

Sift

Benign

0.37

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0

B;.

Vest4

0.012

MVP

0.043

MPC

0.10

ClinPred

0.022

GERP RS

-5.3

Varity_R

0.012

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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