rs4247303

Variant names:

• chr2-85326957-G-A
• rs4247303
• NM_006464.4:c.775C>T
• TGOLN2 p.Arg259Trp

Your query was ambiguous. Multiple possible variants found:

• chr2-85326957-G-A
• chr2-85326957-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -10 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Moderate

The NM_006464.4(TGOLN2):c.775C>T (p.Arg259Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.511 (AC=824,195) in the gnomAD database across 1,613,742 control chromosomes, including 216,905 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.852. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R259P: Uncertain_significance (ClinVar VariationId 3325767, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.49 (19546 hom., cov: 32)
  • Exomes 𝑓: 0.51 (197359 hom.)
• Consequence: TGOLN2 NM_006464.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.30
• Publications: 53 publications found

Genes affected

TGOLN2 (HGNC:15450): (trans-golgi network protein 2) This gene encodes a type I integral membrane protein that is localized to the trans-Golgi network, a major sorting station for secretory and membrane proteins. The encoded protein cycles between early endosomes and the trans-Golgi network, and may play a role in exocytic vesicle formation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011]

ENSG00000307411 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -10 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8521 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006464.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGOLN2	NM_006464.4	MANE Select	c.775C>T	p.Arg259Trp	missense	Exon 2 of 4	NP_006455.2
	TGOLN2	NM_001368095.1		c.775C>T	p.Arg259Trp	missense	Exon 2 of 4	NP_001355024.1	O43493-7
	TGOLN2	NM_001368096.1		c.775C>T	p.Arg259Trp	missense	Exon 2 of 4	NP_001355025.1	A0A5F9UY30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGOLN2	ENST00000377386.8	TSL:1 MANE Select	c.775C>T	p.Arg259Trp	missense	Exon 2 of 4	ENSP00000366603.3	O43493-2
	TGOLN2	ENST00000409015.5	TSL:1	c.775C>T	p.Arg259Trp	missense	Exon 2 of 4	ENSP00000387035.1	O43493-7
	TGOLN2	ENST00000409232.7	TSL:1	c.775C>T	p.Arg259Trp	missense	Exon 2 of 4	ENSP00000386443.3	A0A5F9UY30

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74946 AN: 151926 Hom.: 19532 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.569 AC: 141847 AN: 249228 AF XY: 0.569

Gnomad AFR exome AF: 0.357

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.883

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.513 AC: 749212 AN: 1461698 Hom.: 197359 Cov.: 88 AF XY: 0.516 AC XY: 375140 AN XY: 727124

African (AFR) AF: 0.353 AC: 11824 AN: 33480

American (AMR) AF: 0.706 AC: 31554 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 15650 AN: 26136

East Asian (EAS) AF: 0.858 AC: 34069 AN: 39700

South Asian (SAS) AF: 0.615 AC: 53089 AN: 86258

European-Finnish (FIN) AF: 0.550 AC: 29395 AN: 53398

Middle Eastern (MID) AF: 0.626 AC: 3609 AN: 5768

European-Non Finnish (NFE) AF: 0.484 AC: 537660 AN: 1111860

Other (OTH) AF: 0.536 AC: 32362 AN: 60374

GnomAD4 genome AF: 0.493 AC: 74983 AN: 152044 Hom.: 19546 Cov.: 32 AF XY: 0.504 AC XY: 37429 AN XY: 74286

African (AFR) AF: 0.361 AC: 14962 AN: 41476

American (AMR) AF: 0.627 AC: 9588 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2124 AN: 3470

East Asian (EAS) AF: 0.873 AC: 4510 AN: 5164

South Asian (SAS) AF: 0.610 AC: 2933 AN: 4812

European-Finnish (FIN) AF: 0.557 AC: 5888 AN: 10572

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33193 AN: 67952

Other (OTH) AF: 0.539 AC: 1138 AN: 2110

Alfa AF: 0.503 Hom.: 77758

Bravo AF: 0.497

Asia WGS AF: 0.730 AC: 2536 AN: 3478

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.834 AC: 102390 AN: 122780

Turkish Variome AF: 0.599 AC: 4031 AN: 6724 Hom.: 1221

WBBC (Westlake BioBank for Chinese) pilot AF: 0.880 AC: 7889 AN: 8960 Hom.: 3472

ABraOM SABE-WGS-1171 AF: 0.514 AC: 1204 AN: 2342 Hom.: 328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L
PhyloP100		-5.3
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.081
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.017	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.040
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4247303;

hg19: chr2-85554080;

COSMIC: COSV56407625;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar