2-3387681-C-T

Variant names:

• chr2-3387681-C-T
• rs368311025
• NM_016030.6:c.58C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_016030.6(TRAPPC12):​c.58C>T​(p.Gln20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRAPPC12 NM_016030.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.58C>T	p.Gln20*	stop_gained	Exon 2 of 12	NP_057114.5
	TRAPPC12	NM_001321102.2		c.58C>T	p.Gln20*	stop_gained	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.58C>T	p.Gln20*	stop_gained	Exon 2 of 12	ENSP00000324318.5	Q8WVT3
	TRAPPC12	ENST00000858088.1		c.58C>T	p.Gln20*	stop_gained	Exon 2 of 13	ENSP00000528147.1
	TRAPPC12	ENST00000964175.1		c.58C>T	p.Gln20*	stop_gained	Exon 2 of 13	ENSP00000634234.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000599 AC: 1 AN: 166996 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407650 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695428

African (AFR) AF: 0.00 AC: 0 AN: 31830

American (AMR) AF: 0.00 AC: 0 AN: 36810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 35988

South Asian (SAS) AF: 0.00 AC: 0 AN: 79972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1084210

Other (OTH) AF: 0.00 AC: 0 AN: 58388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000171 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.080	N
PhyloP100		1.8
Vest4		0.11
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=17/183	disease causing (fs/PTC)

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: rs368311025; hg19: chr2-3391452;