X-13713450-CAA-CAAAAAAAAAA

Variant names:

• chrX-13713450-C-CAAAAAAAA
• rs57103709
• NM_001011658.4:c.*956_*957insTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001011658.4(TRAPPC2):​c.*956_*957insTTTTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (3068 hom., 2767 hem., cov: 0)
  • Exomes 𝑓: 0.19 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: TRAPPC2 NM_001011658.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.240
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spondyloepiphyseal dysplasia tarda, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia tarda

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-13713450-C-CAAAAAAAA is Benign according to our data. Variant chrX-13713450-C-CAAAAAAAA is described in ClinVar as Benign. ClinVar VariationId is 367978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 AD,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011658.4. 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
	TRAPPC2	NM_001011658.4	MANE Select	c.*956_*957insTTTTTTTT		3_prime_UTR	Exon 6 of 6	NP_001011658.1	P0DI81-1
	TRAPPC2	NM_001128835.3		c.*956_*957insTTTTTTTT		3_prime_UTR	Exon 6 of 6	NP_001122307.2	P0DI81-3
	TRAPPC2	NM_014563.6		c.*956_*957insTTTTTTTT		3_prime_UTR	Exon 5 of 5	NP_055378.1	P0DI81-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC2	ENST00000380579.6	TSL:1 MANE Select	c.*956_*957insTTTTTTTT		3_prime_UTR	Exon 6 of 6	ENSP00000369953.1	P0DI81-1
	TRAPPC2	ENST00000683983.1		c.*956_*957insTTTTTTTT		3_prime_UTR	Exon 6 of 6	ENSP00000507474.1	P0DI81-3
	TRAPPC2	ENST00000359680.9	TSL:1	c.*956_*957insTTTTTTTT		3_prime_UTR	Exon 5 of 5	ENSP00000352708.5	P0DI81-1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 21793 AN: 83941 Hom.: 3068 Cov.: 0

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.243

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.188 AC: 3 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 2 AN XY: 8

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 1

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.143 AC: 2 AN: 14

Other (OTH) AF: 1.00 AC: 1 AN: 1

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.260 AC: 21786 AN: 83917 Hom.: 3068 Cov.: 0 AF XY: 0.170 AC XY: 2767 AN XY: 16313

African (AFR) AF: 0.286 AC: 5843 AN: 20443

American (AMR) AF: 0.394 AC: 2688 AN: 6818

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 542 AN: 2319

East Asian (EAS) AF: 0.418 AC: 1058 AN: 2534

South Asian (SAS) AF: 0.408 AC: 606 AN: 1487

European-Finnish (FIN) AF: 0.131 AC: 356 AN: 2717

Middle Eastern (MID) AF: 0.237 AC: 38 AN: 160

European-Non Finnish (NFE) AF: 0.225 AC: 10278 AN: 45779

Other (OTH) AF: 0.252 AC: 267 AN: 1061

Alfa AF: 0.0762 Hom.: 392

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spondyloepiphyseal dysplasia congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs57103709;

hg19: chrX-13731569;