rs1553309983

Variant names:

• chr2-3387767-CG-C
• rs1553309983
• NM_016030.6:c.145delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016030.6(TRAPPC12):​c.145delG​(p.Glu49ArgfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRAPPC12 NM_016030.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.27
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 2-3387767-CG-C is Pathogenic according to our data. Variant chr2-3387767-CG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016030.6. 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
	TRAPPC12	NM_016030.6	MANE Select	c.145delG	p.Glu49ArgfsTer14	frameshift	Exon 2 of 12	NP_057114.5
	TRAPPC12	NM_001321102.2		c.145delG	p.Glu49ArgfsTer14	frameshift	Exon 2 of 12	NP_001308031.1	Q8WVT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC12	ENST00000324266.10	TSL:1 MANE Select	c.145delG	p.Glu49ArgfsTer14	frameshift	Exon 2 of 12	ENSP00000324318.5	Q8WVT3
	TRAPPC12	ENST00000858088.1		c.145delG	p.Glu49ArgfsTer14	frameshift	Exon 2 of 13	ENSP00000528147.1
	TRAPPC12	ENST00000964175.1		c.145delG	p.Glu49ArgfsTer14	frameshift	Exon 2 of 13	ENSP00000634234.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
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: rs1553309983; hg19: chr2-3391538;