chrX-13734121-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

The ENST00000683983.1(TRAPPC2):c.12G>A(p.Trp4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 511,094 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00049 ( 0 hom. 73 hem. )

Consequence

TRAPPC2
ENST00000683983.1 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:2

Conservation

PhyloP100: 0.316

Publications

1 publications found

Variant links:

Genes affected

TRAPPC2 (HGNC:23068): (trafficking protein particle complex subunit 2) The protein encoded by this gene is thought to be part of a large multi-subunit complex involved in the targeting and fusion of endoplasmic reticulum-to-Golgi transport vesicles with their acceptor compartment. In addition, the encoded protein can bind c-myc promoter-binding protein 1 and block its transcriptional repression capability. Mutations in this gene are a cause of spondyloepiphyseal dysplasia tarda (SEDT). A processed pseudogene of this gene is located on chromosome 19, and other pseudogenes are found on chromosomes 8 and Y. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2010]

TRAPPC2 links:

OFD1 (HGNC:2567): (OFD1 centriole and centriolar satellite protein) This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]

OFD1 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 10
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome I
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 23
Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome type 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Simpson-Golabi-Behmel syndrome type 2
Inheritance: XL Classification: LIMITED Submitted by: G2P

OFD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000322 (36/111900) while in subpopulation NFE AF = 0.00047 (25/53181). AF 95% confidence interval is 0.000326. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 36 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC2	NM_001011658.4 link	c.-97G>A		5_prime_UTR_variant	Exon 2 of 6	ENST00000380579.6	NP_001011658.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRAPPC2	ENST00000683983.1 link	c.12G>A	p.Trp4*	stop_gained	Exon 2 of 6			ENSP00000507474.1
TRAPPC2	ENST00000380579.6 link	c.-97G>A		5_prime_UTR_variant	Exon 2 of 6	1	NM_001011658.4	ENSP00000369953.1
TRAPPC2	ENST00000359680.9 link	c.-20+404G>A		intron_variant	Intron 1 of 4	1		ENSP00000352708.5
TRAPPC2	ENST00000458511.7 link	c.-90+404G>A		intron_variant	Intron 1 of 5	5		ENSP00000392495.3
TRAPPC2	ENST00000519885.5 link	c.-20+404G>A		intron_variant	Intron 1 of 3	3		ENSP00000430725.1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

111900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000394

AC:

AN:

93930

AF XY:

0.000336

show subpopulations

Gnomad AFR exome

AF:

0.000398

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000678

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000809

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000488

AC:

195

AN:

399194

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

146744

show subpopulations

African (AFR)

AF:

0.0000805

AC:

AN:

12425

American (AMR)

AF:

0.00

AC:

AN:

26775

Ashkenazi Jewish (ASJ)

AF:

0.000688

AC:

AN:

14536

East Asian (EAS)

AF:

0.00

AC:

AN:

24035

South Asian (SAS)

AF:

0.00

AC:

AN:

37337

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25607

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2970

European-Non Finnish (NFE)

AF:

0.000731

AC:

170

AN:

232483

Other (OTH)

AF:

0.000608

AC:

AN:

23026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000322

AC:

AN:

111900

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34084

show subpopulations

African (AFR)

AF:

0.000261

AC:

AN:

30699

American (AMR)

AF:

0.00

AC:

AN:

10594

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6105

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

53181

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000692

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.000125

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spondyloepiphyseal dysplasia tarda

Pathogenic:2Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 08, 2014

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 04, 2016

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRAPPC2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

7.0

(source)

DANN

Benign

0.97

FATHMM_MKL

Benign

0.0088

PhyloP100

0.32

Vest4

0.28

GERP RS

-0.14

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=174/26

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over