Variant X-41727717-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_080817.5(GPR82):c.691A>G(p.Ile231Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,202,649 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000035 ( 0 hom. 14 hem. )

Consequence

GPR82
NM_080817.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.670

Variant links:

Genes affected

GPR82 (HGNC:4533): (G protein-coupled receptor 82) The protein encoded by this gene is an orphan G protein-coupled receptor of unknown function. The encoded protein is a member of a family of proteins that contain seven transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. [provided by RefSeq, Sep 2011]

GPR82 links:

CASK (HGNC:1497): (calcium/calmodulin dependent serine protein kinase) This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

CASK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012476206).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR82	NM_080817.5 linkuse as main transcript	c.691A>G	p.Ile231Val	missense_variant	3/3	ENST00000302548.5
CASK	NM_001367721.1 linkuse as main transcript	c.429+11667T>C		intron_variant		ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR82	ENST00000302548.5 linkuse as main transcript	c.691A>G	p.Ile231Val	missense_variant	3/3	1	NM_080817.5	P1
CASK	ENST00000378163.7 linkuse as main transcript	c.429+11667T>C		intron_variant		5	NM_001367721.1	A1	O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

112105

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34257

show subpopulations

Gnomad AFR

AF:

0.000519

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000742

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000665

GnomAD3 exomes

AF:

0.000121

AC:

AN:

182488

Hom.:

AF XY:

0.0000597

AC XY:

AN XY:

67010

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000268

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.000890

GnomAD4 exome

AF:

0.0000348

AC:

AN:

1090490

Hom.:

Cov.:

AF XY:

0.0000393

AC XY:

AN XY:

356060

show subpopulations

Gnomad4 AFR exome

AF:

0.000457

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000242

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000239

Gnomad4 OTH exome

AF:

0.0000872

GnomAD4 genome

AF:

0.000187

AC:

AN:

112159

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34321

show subpopulations

Gnomad4 AFR

AF:

0.000518

Gnomad4 AMR

AF:

0.000189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000744

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.691A>G (p.I231V) alteration is located in exon 3 (coding exon 1) of the GPR82 gene. This alteration results from a A to G substitution at nucleotide position 691, causing the isoleucine (I) at amino acid position 231 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.89

CADD

Benign

9.5

DANN

Benign

0.76

DEOGEN2

Benign

0.052

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.43

M_CAP

Benign

0.0062

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.030

REVEL

Benign

0.041

Sift

Benign

0.86

Sift4G

Benign

0.28

Polyphen

0.0030

Vest4

0.015

MVP

0.39

MPC

0.15

ClinPred

0.0075

GERP RS

2.1

Varity_R

0.037

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over