NM_016030.6:c.681T>C

Variant names:

• chr2-3388304-T-C
• rs10865541
• NM_016030.6:c.681T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016030.6(TRAPPC12):​c.681T>C​(p.Phe227Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,606,390 control chromosomes in the GnomAD database, including 284,338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29565 hom., cov: 32)
  • Exomes 𝑓: 0.59 (254773 hom.)
• Consequence: TRAPPC12 NM_016030.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.72
• Publications: 26 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-3388304-T-C is Benign according to our data. Variant chr2-3388304-T-C is described in ClinVar as Benign. ClinVar VariationId is 1282559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

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.681T>C	p.Phe227Phe	synonymous	Exon 2 of 12	NP_057114.5
	TRAPPC12	NM_001321102.2		c.681T>C	p.Phe227Phe	synonymous	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.681T>C	p.Phe227Phe	synonymous	Exon 2 of 12	ENSP00000324318.5	Q8WVT3
	TRAPPC12	ENST00000858088.1		c.681T>C	p.Phe227Phe	synonymous	Exon 2 of 13	ENSP00000528147.1
	TRAPPC12	ENST00000964175.1		c.681T>C	p.Phe227Phe	synonymous	Exon 2 of 13	ENSP00000634234.1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94259 AN: 151804 Hom.: 29529 Cov.: 32

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.696

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.617

GnomAD2 exomes AF: 0.596 AC: 140587 AN: 235766 AF XY: 0.601

Gnomad AFR exome AF: 0.700

Gnomad AMR exome AF: 0.461

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.714

Gnomad FIN exome AF: 0.615

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.591 AC: 858899 AN: 1454478 Hom.: 254773 Cov.: 62 AF XY: 0.592 AC XY: 428628 AN XY: 723560

African (AFR) AF: 0.703 AC: 22654 AN: 32224

American (AMR) AF: 0.470 AC: 20784 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 16297 AN: 25856

East Asian (EAS) AF: 0.677 AC: 26402 AN: 38974

South Asian (SAS) AF: 0.651 AC: 55681 AN: 85476

European-Finnish (FIN) AF: 0.613 AC: 32358 AN: 52812

Middle Eastern (MID) AF: 0.667 AC: 3825 AN: 5734

European-Non Finnish (NFE) AF: 0.581 AC: 644342 AN: 1109088

Other (OTH) AF: 0.608 AC: 36556 AN: 60086

GnomAD4 genome AF: 0.621 AC: 94329 AN: 151912 Hom.: 29565 Cov.: 32 AF XY: 0.621 AC XY: 46145 AN XY: 74254

African (AFR) AF: 0.704 AC: 29181 AN: 41468

American (AMR) AF: 0.529 AC: 8088 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2178 AN: 3470

East Asian (EAS) AF: 0.695 AC: 3545 AN: 5098

South Asian (SAS) AF: 0.652 AC: 3143 AN: 4824

European-Finnish (FIN) AF: 0.616 AC: 6514 AN: 10578

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.582 AC: 39491 AN: 67886

Other (OTH) AF: 0.612 AC: 1288 AN: 2106

Alfa AF: 0.598 Hom.: 55155

Bravo AF: 0.617

Asia WGS AF: 0.679 AC: 2345 AN: 3452

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome (1)
-	-	1	TRAPPC12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.5
DANN	Benign	0.43
PhyloP100		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs10865541; hg19: chr2-3392075; COSMIC: COSV60844897; COSMIC: COSV60844897;