X-41727085-T-C

Variant names:

• chrX-41727085-T-C
• rs369077460
• NM_080817.5:c.59T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_080817.5(GPR82):​c.59T>C​(p.Ile20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000773 in 1,164,423 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000057 (0 hom. 2 hem.)
• Consequence: GPR82 NM_080817.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12076974).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR82	NM_080817.5	c.59T>C	p.Ile20Thr	missense_variant	Exon 3 of 3	ENST00000302548.5	NP_543007.1
CASK	NM_001367721.1	c.429+12299A>G		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	c.59T>C	p.Ile20Thr	missense_variant	Exon 3 of 3	1	NM_080817.5	ENSP00000303549.4
CASK	ENST00000378163.7	c.429+12299A>G		intron_variant	Intron 5 of 26	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112019 Hom.: 0 Cov.: 24 AF XY: 0.0000585 AC XY: 2 AN XY: 34163

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000554

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000168 AC: 3 AN: 178753 Hom.: 0 AF XY: 0.0000315 AC XY: 2 AN XY: 63489

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000145

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: 0.00000570 AC: 6 AN: 1052352 Hom.: 0 Cov.: 23 AF XY: 0.00000619 AC XY: 2 AN XY: 323236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000449

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112071 Hom.: 0 Cov.: 24 AF XY: 0.0000584 AC XY: 2 AN XY: 34225

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000556

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59T>C (p.I20T) alteration is located in exon 3 (coding exon 1) of the GPR82 gene. This alteration results from a T to C substitution at nucleotide position 59, causing the isoleucine (I) at amino acid position 20 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.4
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.087	T
Sift4G	Uncertain	0.011	D
Polyphen		0.19	B
Vest4		0.24
MutPred		0.49		Gain of glycosylation at I20 (P = 0.0254);
MVP		0.35
MPC		0.31
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.085

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: rs369077460; hg19: chrX-41586338;