chrX-41696521-A-G

Position:

• chrX-41696521-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001097579.2(GPR34):​c.888A>G​(p.Val296Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,206,888 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,041 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., 55 hem., cov: 23)
  • Exomes 𝑓: 0.0028 (9 hom. 986 hem.)
• Consequence: GPR34 NM_001097579.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07

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]

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-41696521-A-G is Benign according to our data. Variant chrX-41696521-A-G is described in ClinVar as [Benign]. Clinvar id is 713839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR34	NM_001097579.2	c.888A>G	p.Val296Val	synonymous_variant	3/3	ENST00000378142.9	NP_001091048.1
CASK	NM_001367721.1	c.430-24991T>C		intron_variant		ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR34	ENST00000378142.9	c.888A>G	p.Val296Val	synonymous_variant	3/3	1	NM_001097579.2	ENSP00000367384.4
CASK	ENST00000378163.7	c.430-24991T>C		intron_variant		5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 223 AN: 112168 Hom.: 2 Cov.: 23 AF XY: 0.00160 AC XY: 55 AN XY: 34308

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.00327

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.00225 AC: 411 AN: 182524 Hom.: 0 AF XY: 0.00217 AC XY: 146 AN XY: 67216

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000526

Gnomad FIN exome AF: 0.00252

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00279 AC: 3050 AN: 1094665 Hom.: 9 Cov.: 30 AF XY: 0.00274 AC XY: 986 AN XY: 360231

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.000413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000611

Gnomad4 FIN exome AF: 0.00267

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00199 AC: 223 AN: 112223 Hom.: 2 Cov.: 23 AF XY: 0.00160 AC XY: 55 AN XY: 34373

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00143

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00327

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.00265 Hom.: 19

Bravo AF: 0.00184

EpiCase AF: 0.00208

EpiControl AF: 0.00232

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.54

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: rs138580045; hg19: chrX-41555774;