17-46923196-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004287.5(GOSR2):c.4G>A(p.Asp2Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000043 in 1,394,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: GOSR2 NM_004287.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41326144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GOSR2	NM_004287.5	c.4G>A	p.Asp2Asn	missense_variant	1/6	ENST00000640051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GOSR2	ENST00000640051.2	c.4G>A	p.Asp2Asn	missense_variant	1/6	1	NM_004287.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000648 AC: 1 AN: 154336 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81640

Gnomad AFR exome AF: 0.000119

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1394944 Hom.: 0 Cov.: 30 AF XY: 0.00000291 AC XY: 2 AN XY: 688320

Gnomad4 AFR exome AF: 0.0000317

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: 0.00000465

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jun 10, 2021

This variant has not been reported in the literature in individuals with GOSR2-related conditions. 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 2 of the GOSR2 protein (p.Asp2Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0017
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.70	T
Polyphen		0.046, 0.011	.;.;.;B;.;.;B;.;.;.;.;.;.;.
Vest4		0.31, 0.32, 0.22, 0.35
MutPred		0.57		Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);Gain of MoRF binding (P = 0.1491);
MVP		0.70
MPC		0.17
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.25
gMVP		0.10

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: rs1425442098; hg19: chr17-45000562; COSMIC: COSV56662396; COSMIC: COSV56662396;