X-41727717-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.670

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]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012476206).
• BS2: High Hemizygotes in GnomAd at 6 gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 21 AN: 112105 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34257

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: 22 AN: 182488 Hom.: 1 AF XY: 0.0000597 AC XY: 4 AN XY: 67010

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: 38 AN: 1090490 Hom.: 0 Cov.: 28 AF XY: 0.0000393 AC XY: 14 AN XY: 356060

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: 21 AN: 112159 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34321

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.: 0

Bravo AF: 0.000193

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	9.5
Dann	Benign	0.76
DEOGEN2	Benign	0.052	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.041
Sift	Benign	0.86	T
Sift4G	Benign	0.28	T
Polyphen		0.0030	B
Vest4		0.015
MVP		0.39
MPC		0.15
ClinPred		0.0075	T
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

Other links and lift over

dbSNP: rs745907529; hg19: chrX-41586970;