2-3387768-G-A

Variant names:

• chr2-3387768-G-A
• rs117747228
• NM_016030.6:c.145G>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.145G>A​(p.Glu49Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000732 in 1,612,926 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: TRAPPC12 NM_016030.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.27

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=0.0049600303).
• BP6: Variant 2-3387768-G-A is Benign according to our data. Variant chr2-3387768-G-A is described in ClinVar as [Benign]. Clinvar id is 1530005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000893 (136/152356) while in subpopulation EAS AF= 0.0162 (84/5188). AF 95% confidence interval is 0.0134. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC12	NM_016030.6	c.145G>A	p.Glu49Lys	missense_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.145G>A	p.Glu49Lys	missense_variant	Exon 2 of 12	1	NM_016030.6	ENSP00000324318.5
TRAPPC12	ENST00000382110.6	c.145G>A	p.Glu49Lys	missense_variant	Exon 2 of 12	2		ENSP00000371544.2
TRAPPC12	ENST00000482645.1	n.306G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00185 AC: 459 AN: 248264 Hom.: 4 AF XY: 0.00155 AC XY: 208 AN XY: 134372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.000715 AC: 1045 AN: 1460570 Hom.: 2 Cov.: 31 AF XY: 0.000644 AC XY: 468 AN XY: 726506

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00538

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0164

Gnomad4 SAS exome AF: 0.000407

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74510

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000626 Hom.: 1

Bravo AF: 0.00104

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TRAPPC12-related disorder Benign:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	.;D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.093
Sift	Benign	0.042	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.98	D;D
Vest4		0.22
MVP		0.62
MPC		0.48
ClinPred		0.060	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.20

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: rs117747228; hg19: chr2-3391539;