17-46923195-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_004287.5(GOSR2):c.3G>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000717 in 1,394,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GOSR2 NM_004287.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

GOSR2 (HGNC:4431): (golgi SNAP receptor complex member 2) This gene encodes a trafficking membrane protein which transports proteins among the medial- and trans-Golgi compartments. Due to its chromosomal location and trafficking function, this gene may be involved in familial essential hypertension. [provided by RefSeq, Mar 2016]

LRRC37A2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004287.5 (GOSR2) was described as [Pathogenic] in ClinVar as 1324496
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GOSR2	NM_004287.5	c.3G>T	p.Met1?	start_lost	1/6	ENST00000640051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GOSR2	ENST00000640051.2	c.3G>T	p.Met1?	start_lost	1/6	1	NM_004287.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394166 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687936

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: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Disruption of the initiator codon has been observed in individual(s) with clinical features of GOSR2-related conditions (PMID: 29855340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GOSR2 mRNA. The next in-frame methionine is located at codon 19. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
Polyphen		0.89, 0.32	.;.;.;P;.;.;B;.;.;.;.;.;.;.
Vest4		0.78, 0.78, 0.79, 0.77
MutPred		0.83		Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);Gain of catalytic residue at M1 (P = 0.0328);
MVP		0.82
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1174104260; hg19: chr17-45000561;