17-46923195-G-A

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>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000143 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: 0.0000014 (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>A	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>A	p.Met1?	start_lost	1/6	1	NM_004287.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 687936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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

Jan 20, 2020

This sequence change affects the initiator methionine of the GOSR2 mRNA. The next in-frame methionine is located at codon 19. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with GOSR2-related conditions. This variant is not present in population databases (ExAC no frequency). -

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	0.79	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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-45000561; COSMIC: COSV56664831; COSMIC: COSV56664831;