2-3387687-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016030.6(TRAPPC12):c.64G>A(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,565,924 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (15 hom.)
• Consequence: TRAPPC12 NM_016030.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.626

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035474598).
• BP6: Variant 2-3387687-G-A is Benign according to our data. Variant chr2-3387687-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1614588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00224 (341/152292) while in subpopulation AMR AF= 0.00379 (58/15308). AF 95% confidence interval is 0.00301. There are 2 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC12	NM_016030.6	c.64G>A	p.Ala22Thr	missense_variant	2/12	ENST00000324266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC12	ENST00000324266.10	c.64G>A	p.Ala22Thr	missense_variant	2/12	1	NM_016030.6	P1
TRAPPC12	ENST00000382110.6	c.64G>A	p.Ala22Thr	missense_variant	2/12	2		P1
TRAPPC12	ENST00000482645.1	n.225G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00280 AC: 492 AN: 175864 Hom.: 4 AF XY: 0.00298 AC XY: 281 AN XY: 94410

Gnomad AFR exome AF: 0.000412

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.000805

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00481

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00252 AC: 3556 AN: 1413632 Hom.: 15 Cov.: 31 AF XY: 0.00258 AC XY: 1802 AN XY: 699028

Gnomad4 AFR exome AF: 0.000876

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.000435

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.00563

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152292 Hom.: 2 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74472

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00228 Hom.: 2

Bravo AF: 0.00186

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000458 AC: 2

ESP6500EA AF: 0.00292 AC: 25

ExAC AF: 0.00205 AC: 244

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TRAPPC12: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

TRAPPC12-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.1
Dann	Benign	0.80
DEOGEN2	Benign	0.0031	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.024	N
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.77	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.071
Sift	Benign	0.40	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.43	B;B
Vest4		0.032
MVP		0.46
MPC		0.24
ClinPred		0.0015	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.067

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

LitVar

Other links and lift over

dbSNP: rs200941005; hg19: chr2-3391458; COSMIC: COSV60848589; COSMIC: COSV60848589;