NM_080817.5:c.100A>G

Variant names:

• chrX-41727126-A-G
• rs200780473
• NM_080817.5:c.100A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080817.5(GPR82):​c.100A>G​(p.Thr34Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000927 in 1,078,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T34S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: GPR82 NM_080817.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.811
• Publications: 0 publications found

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]

CASK Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0963085).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080817.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR82	NM_080817.5	MANE Select	c.100A>G	p.Thr34Ala	missense	Exon 3 of 3	NP_543007.1	Q96P67
	CASK	NM_001367721.1	MANE Select	c.429+12258T>C		intron	N/A	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.429+12258T>C		intron	N/A	NP_003679.2	O14936-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR82	ENST00000302548.5	TSL:1 MANE Select	c.100A>G	p.Thr34Ala	missense	Exon 3 of 3	ENSP00000303549.4	Q96P67
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.429+12258T>C		intron	N/A	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.447+12258T>C		intron	N/A	ENSP00000400526.4	A0A7I2RJN6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.27e-7 AC: 1 AN: 1078928 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 345716

African (AFR) AF: 0.00 AC: 0 AN: 26056

American (AMR) AF: 0.00 AC: 0 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19245

East Asian (EAS) AF: 0.00 AC: 0 AN: 30082

South Asian (SAS) AF: 0.00 AC: 0 AN: 53542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40513

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 824796

Other (OTH) AF: 0.00 AC: 0 AN: 45484

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.63
DEOGEN2	Benign	0.041	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.81
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.024
Sift	Benign	0.60	T
Sift4G	Benign	0.24	T
Polyphen		0.0070	B
Vest4		0.046
MutPred		0.56		Gain of sheet (P = 0.1208)
MVP		0.47
MPC		0.17
ClinPred		0.022	T
GERP RS		1.6
Varity_R		0.034
gMVP		0.028
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs200780473; hg19: chrX-41586379;