chrX-41696517-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001097579.2(GPR34):c.884A>G(p.Asn295Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,207,802 control chromosomes in the GnomAD database, including 88 homozygotes. There are 1,139 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 35 hom., 528 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 53 hom. 611 hem. )

Consequence

GPR34
NM_001097579.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.20

Publications

0 publications found

Variant links:

Genes affected

GPR34 (HGNC:4490): (G protein-coupled receptor 34) G protein-coupled receptors (GPCRs), such as GPR34, are integral membrane proteins containing 7 putative transmembrane domains (TMs). These proteins mediate signals to the interior of the cell via activation of heterotrimeric G proteins that in turn activate various effector proteins, ultimately resulting in a physiologic response.[supplied by OMIM, Apr 2006]

GPR34 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 Gene-Disease associations (from GenCC):

FG syndrome 4
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
syndromic X-linked intellectual disability Najm type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CASK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028212368).

BP6

Variant X-41696517-A-G is Benign according to our data. Variant chrX-41696517-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR34	NM_001097579.2 link	c.884A>G	p.Asn295Ser	missense_variant	Exon 3 of 3	ENST00000378142.9	NP_001091048.1	Q9UPC5Q5VT14
CASK	NM_001367721.1 link	c.430-24987T>C		intron_variant	Intron 5 of 26	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR34	ENST00000378142.9 link	c.884A>G	p.Asn295Ser	missense_variant	Exon 3 of 3	1	NM_001097579.2	ENSP00000367384.4		Q9UPC5
CASK	ENST00000378163.7 link	c.430-24987T>C		intron_variant	Intron 5 of 26	5	NM_001367721.1	ENSP00000367405.1		O14936-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

1935

AN:

112017

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.000225

Gnomad OTH

AF:

0.0146

GnomAD2 exomes

AF:

0.00530

AC:

968

AN:

182555

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.00409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.00202

AC:

2218

AN:

1095731

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

611

AN XY:

361245

show subpopulations

African (AFR)

AF:

0.0649

AC:

1711

AN:

26352

American (AMR)

AF:

0.00480

AC:

169

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19356

East Asian (EAS)

AF:

0.00

AC:

AN:

30163

South Asian (SAS)

AF:

0.000203

AC:

AN:

54057

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40407

Middle Eastern (MID)

AF:

0.00509

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.000102

AC:

AN:

840072

Other (OTH)

AF:

0.00478

AC:

220

AN:

46010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0173

AC:

1938

AN:

112071

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

528

AN XY:

34233

show subpopulations

African (AFR)

AF:

0.0578

AC:

1787

AN:

30895

American (AMR)

AF:

0.0109

AC:

114

AN:

10506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.000369

AC:

AN:

2712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6067

Middle Eastern (MID)

AF:

0.00922

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000225

AC:

AN:

53220

Other (OTH)

AF:

0.0144

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

142

214

285

356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00565

Hom.:

300

Bravo

AF:

0.0214

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.0602

AC:

231

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00591

AC:

718

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 28, 2015

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.91

CADD

Benign

8.5

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.055

T;T;.;T

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.74

.;.;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.93

L;L;.;L

PhyloP100

1.2

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.28

N;N;.;.

REVEL

Benign

0.033

Sift

Benign

0.28

T;T;.;.

Sift4G

Benign

0.59

T;T;T;.

Polyphen

0.014

B;B;.;B

Vest4

0.034

MVP

0.53

MPC

0.56

ClinPred

0.0071

GERP RS

3.3

Varity_R

0.064

gMVP

0.098

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over