rs1135401749

Variant names:

• chr2-3387978-G-GC
• rs1135401749
• NM_016030.6:c.360dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016030.6(TRAPPC12):​c.360dupC​(p.Glu121ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,322,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: TRAPPC12 NM_016030.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.28
• Publications: 1 publications found

Genes affected

TRAPPC12 (HGNC:24284): (trafficking protein particle complex subunit 12) Involved in several processes, including endoplasmic reticulum to Golgi vesicle-mediated transport; positive regulation of protein localization to kinetochore; and regulation of kinetochore assembly. Located in Golgi apparatus; kinetochore; and nucleoplasm. Part of TRAPP complex. Colocalizes with endoplasmic reticulum-Golgi intermediate compartment and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC12 Gene-Disease associations (from GenCC):

• early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-3387978-G-GC is Pathogenic according to our data. Variant chr2-3387978-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 430822.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC12	NM_016030.6	c.360dupC	p.Glu121ArgfsTer7	frameshift_variant	Exon 2 of 12	ENST00000324266.10	NP_057114.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC12	ENST00000324266.10	c.360dupC	p.Glu121ArgfsTer7	frameshift_variant	Exon 2 of 12	1	NM_016030.6	ENSP00000324318.5
TRAPPC12	ENST00000382110.6	c.360dupC	p.Glu121ArgfsTer7	frameshift_variant	Exon 2 of 12	2		ENSP00000371544.2
TRAPPC12	ENST00000482645.1	n.521dupC		non_coding_transcript_exon_variant	Exon 2 of 2	2
TRAPPC12	ENST00000411973.3	n.-150_-149insC		upstream_gene_variant		5		ENSP00000405626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000454 AC: 6 AN: 1322730 Hom.: 0 Cov.: 30 AF XY: 0.00000462 AC XY: 3 AN XY: 649712

African (AFR) AF: 0.00 AC: 0 AN: 26630

American (AMR) AF: 0.00 AC: 0 AN: 24584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21262

East Asian (EAS) AF: 0.00 AC: 0 AN: 31858

South Asian (SAS) AF: 0.00 AC: 0 AN: 70500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4718

European-Non Finnish (NFE) AF: 0.00000571 AC: 6 AN: 1051208

Other (OTH) AF: 0.00 AC: 0 AN: 54608

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome Pathogenic:1

Sep 18, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Progressive childhood encephalopathy Pathogenic:1

May 01, 2017

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

TRAPPC12-related disorder Pathogenic:1

Jan 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TRAPPC12 c.360dupC variant is predicted to result in a frameshift and premature protein termination (p.Glu121Argfs*7). This variant has been reported in the compound heterozygous state in two siblings with progressive childhood encephalopathy and golgi dysfunction (Milev et al. 2017. PubMed ID: 28777934). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in TRAPPC12 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1135401749; hg19: chr2-3391749;