X-41727704-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_080817.5(GPR82):c.678C>A(p.Ser226Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,196,788 control chromosomes in the GnomAD database, including 1 homozygotes. There are 100 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00028 ( 1 hom. 94 hem. )

Consequence

GPR82
NM_080817.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.123

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005873412).

BP6

Variant X-41727704-C-A is Benign according to our data. Variant chrX-41727704-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 445537.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR82	NM_080817.5 link	c.678C>A	p.Ser226Arg	missense_variant	Exon 3 of 3	ENST00000302548.5	NP_543007.1	Q96P67
CASK	NM_001367721.1 link	c.429+11680G>T		intron_variant	Intron 5 of 26	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR82	ENST00000302548.5 link	c.678C>A	p.Ser226Arg	missense_variant	Exon 3 of 3	1	NM_080817.5	ENSP00000303549.4		Q96P67
CASK	ENST00000378163.7 link	c.429+11680G>T		intron_variant	Intron 5 of 26	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

111633

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

33861

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000952

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.00101

AC:

184

AN:

182392

Hom.:

AF XY:

0.000897

AC XY:

AN XY:

66914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0133

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:

0.000278

AC:

302

AN:

1085101

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

351189

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00923

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000120

Gnomad4 OTH exome

AF:

0.000503

GnomAD4 genome

AF:

0.000340

AC:

AN:

111687

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

33925

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00980

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.000435

Hom.:

Bravo

AF:

0.000370

ExAC

AF:

0.000766

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.4

DANN

Benign

0.78

DEOGEN2

Benign

0.040

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.46

PrimateAI

Benign

0.38

PROVEAN

Benign

0.86

REVEL

Benign

0.062

Sift

Benign

0.64

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.18

MutPred

0.67

Gain of MoRF binding (P = 0.0108);

MVP

0.24

MPC

0.20

ClinPred

0.014

GERP RS

0.60

Varity_R

0.19

gMVP

0.20

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