17-46923199-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004287.5(GOSR2):c.7C>T(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,547,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. P3L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

GOSR2
NM_004287.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.947

Publications

6 publications found

Variant links:

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]

GOSR2 links:

ENSG00000262633 (HGNC:):

ENSG00000262633 links:

LRRC37A2 (HGNC:32404): (leucine rich repeat containing 37 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC37A2 links:

GOSR2-DT (HGNC:55346): (GOSR2 divergent transcript)

GOSR2-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09946698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOSR2	NM_004287.5 link	c.7C>T	p.Pro3Ser	missense_variant	Exon 1 of 6	ENST00000640051.2	NP_004278.2	O14653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOSR2	ENST00000640051.2 link	c.7C>T	p.Pro3Ser	missense_variant	Exon 1 of 6	1	NM_004287.5	ENSP00000492751.1		O14653-1
ENSG00000262633	ENST00000571841.1 link	n.7C>T		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000461460.1		E7EQ34

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

154338

AF XY:

0.0000245

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000244

AC:

AN:

1394986

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

688312

show subpopulations

African (AFR)

AF:

0.0000635

AC:

AN:

31518

American (AMR)

AF:

0.00

AC:

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25126

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35708

South Asian (SAS)

AF:

0.0000506

AC:

AN:

79128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49130

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000186

AC:

AN:

1075164

Other (OTH)

AF:

0.0000691

AC:

AN:

57860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68052

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

128

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 12, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Progressive myoclonic epilepsy

Uncertain:1

Mar 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the GOSR2 protein (p.Pro3Ser). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GOSR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1036487). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0045

.;.;.;.;.;.;T;.;.;.;.;.;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.43

T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.099

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.27

.;.;.;N;.;.;N;.;N;.;.;.;.;.

PhyloP100

0.95

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.76

.;.;.;N;N;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.81

.;.;.;T;T;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.65

.;.;.;T;T;T;.;.;.;.;T;.;.;.

Polyphen

0.0

.;.;.;B;.;.;B;.;.;.;.;.;.;.

Vest4

0.34, 0.33, 0.33, 0.35

MutPred

0.25

Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);Loss of catalytic residue at P3 (P = 0.0056);

MVP

0.65

MPC

0.17

ClinPred

0.043

GERP RS

4.0

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.099

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over