X-41727580-G-A

Position:

• chrX-41727580-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_080817.5(GPR82):​c.554G>A​(p.Ser185Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 1,195,430 control chromosomes in the GnomAD database, including 3 homozygotes. There are 209 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 0.0038 (3 hom., 99 hem., cov: 23)
  • Exomes 𝑓: 0.00035 (0 hom. 110 hem.)
• Consequence: GPR82 NM_080817.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.936

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027709603).
• BP6: Variant X-41727580-G-A is Benign according to our data. Variant chrX-41727580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR82	NM_080817.5	c.554G>A	p.Ser185Asn	missense_variant	3/3	ENST00000302548.5
CASK	NM_001367721.1	c.429+11804C>T		intron_variant		ENST00000378163.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR82	ENST00000302548.5	c.554G>A	p.Ser185Asn	missense_variant	3/3	1	NM_080817.5	P1
CASK	ENST00000378163.7	c.429+11804C>T		intron_variant		5	NM_001367721.1	A1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 421 AN: 111845 Hom.: 3 Cov.: 23 AF XY: 0.00282 AC XY: 96 AN XY: 34017

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00332

GnomAD3 exomes AF: 0.00104 AC: 191 AN: 183021 Hom.: 0 AF XY: 0.000666 AC XY: 45 AN XY: 67575

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000621

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000351 AC: 380 AN: 1083534 Hom.: 0 Cov.: 28 AF XY: 0.000313 AC XY: 110 AN XY: 351344

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000181

Gnomad4 OTH exome AF: 0.000724

GnomAD4 genome AF: 0.00379 AC: 424 AN: 111896 Hom.: 3 Cov.: 23 AF XY: 0.00291 AC XY: 99 AN XY: 34078

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00327

Alfa AF: 0.000375 Hom.: 18

Bravo AF: 0.00436

ESP6500AA AF: 0.0167 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00129 AC: 157

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.024
DANN	Benign	0.61
DEOGEN2	Benign	0.066	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.070
Sift	Benign	0.52	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.017
MVP		0.067
MPC		0.16
ClinPred		0.0038	T
GERP RS		-6.1
Varity_R		0.057
gMVP		0.16

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: rs146786893; hg19: chrX-41586833;