2-85327283-C-A

Position:

• chr2-85327283-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006464.4(TGOLN2):​c.449G>T​(p.Ser150Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TGOLN2 NM_006464.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.82

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06683877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGOLN2	NM_006464.4	c.449G>T	p.Ser150Ile	missense_variant	2/4	ENST00000377386.8	NP_006455.2
TGOLN2	NM_001368095.1	c.449G>T	p.Ser150Ile	missense_variant	2/4		NP_001355024.1
TGOLN2	NM_001368096.1	c.449G>T	p.Ser150Ile	missense_variant	2/4		NP_001355025.1
TGOLN2	NM_001206844.2	c.449G>T	p.Ser150Ile	missense_variant	2/5		NP_001193773.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGOLN2	ENST00000377386.8	c.449G>T	p.Ser150Ile	missense_variant	2/4	1	NM_006464.4	ENSP00000366603.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459038 Hom.: 0 Cov.: 37 AF XY: 0.00000413 AC XY: 3 AN XY: 725788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2023

The c.449G>T (p.S150I) alteration is located in exon 2 (coding exon 2) of the TGOLN2 gene. This alteration results from a G to T substitution at nucleotide position 449, causing the serine (S) at amino acid position 150 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.43	.;T;T;.;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.067	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.0050
Sift	Uncertain	0.0080	D;T;T;D;D;D
Sift4G	Benign	0.073	T;T;T;T;T;T
Polyphen		0.13	B;B;B;.;.;B
Vest4		0.10
MutPred		0.18		Loss of phosphorylation at S150 (P = 0.005);Loss of phosphorylation at S150 (P = 0.005);Loss of phosphorylation at S150 (P = 0.005);Loss of phosphorylation at S150 (P = 0.005);Loss of phosphorylation at S150 (P = 0.005);Loss of phosphorylation at S150 (P = 0.005);
MVP		0.081
ClinPred		0.20	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.038
gMVP		0.071

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: rs200759061; hg19: chr2-85554406;