17-46923199-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004287.5(GOSR2):c.7C>A(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,546,906 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 33)
  • Exomes 𝑓: 0.024 (489 hom.)
• Consequence: GOSR2 NM_004287.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.947

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032203794).
• BP6: Variant 17-46923199-C-A is Benign according to our data. Variant chr17-46923199-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 137488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46923199-C-A is described in Lovd as [Benign]. Variant chr17-46923199-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0181 (2765/152350) while in subpopulation NFE AF= 0.0235 (1602/68044). AF 95% confidence interval is 0.0226. There are 45 homozygotes in gnomad4. There are 1391 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GOSR2	NM_004287.5	c.7C>A	p.Pro3Thr	missense_variant	1/6	ENST00000640051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GOSR2	ENST00000640051.2	c.7C>A	p.Pro3Thr	missense_variant	1/6	1	NM_004287.5	P3

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2766 AN: 152232 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0224 AC: 3462 AN: 154338 Hom.: 67 AF XY: 0.0237 AC XY: 1938 AN XY: 81616

Gnomad AFR exome AF: 0.00334

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.000621

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0235 AC: 32809 AN: 1394556 Hom.: 489 Cov.: 30 AF XY: 0.0238 AC XY: 16356 AN XY: 688094

Gnomad4 AFR exome AF: 0.00349

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0657

Gnomad4 EAS exome AF: 0.00193

Gnomad4 SAS exome AF: 0.0253

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0181 AC: 2765 AN: 152350 Hom.: 45 Cov.: 33 AF XY: 0.0187 AC XY: 1391 AN XY: 74500

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.0683

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0222 Hom.: 51

Bravo AF: 0.0164

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00345 AC: 12

ESP6500EA AF: 0.0179 AC: 116

ExAC AF: 0.0171 AC: 539

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Progressive myoclonic epilepsy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	10
Dann	Benign	0.81
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.69	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
Polyphen		0.0	.;.;.;B;.;.;B;.;.;.;.;.;.;.
Vest4		0.23, 0.22, 0.090, 0.23
MPC		0.19
ClinPred		0.0083	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
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: rs12944167; hg19: chr17-45000565; COSMIC: COSV56661101; COSMIC: COSV56661101;