rs61746390

Variant names:

• chrX-41696517-A-G
• rs61746390
• NM_001097579.2:c.884A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N295D) has been classified as Uncertain significance.

• 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20
• Publications: 0 publications found

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 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: 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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001097579.2. 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
	GPR34	NM_001097579.2	MANE Select	c.884A>G	p.Asn295Ser	missense	Exon 3 of 3	NP_001091048.1	Q9UPC5
	CASK	NM_001367721.1	MANE Select	c.430-24987T>C		intron	N/A	NP_001354650.1	O14936-1
	GPR34	NM_005300.4		c.884A>G	p.Asn295Ser	missense	Exon 3 of 3	NP_005291.1	Q5VT14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR34	ENST00000378142.9	TSL:1 MANE Select	c.884A>G	p.Asn295Ser	missense	Exon 3 of 3	ENSP00000367384.4	Q9UPC5
	GPR34	ENST00000378138.5	TSL:1	c.884A>G	p.Asn295Ser	missense	Exon 3 of 3	ENSP00000367378.5	Q9UPC5
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.430-24987T>C		intron	N/A	ENSP00000367405.1	O14936-1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 1935 AN: 112017 Hom.: 35 Cov.: 23

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

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.: 53 Cov.: 30 AF XY: 0.00169 AC XY: 611 AN XY: 361245

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: 0 AN: 19356

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.000203 AC: 11 AN: 54057

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40407

Middle Eastern (MID) AF: 0.00509 AC: 21 AN: 4128

European-Non Finnish (NFE) AF: 0.000102 AC: 86 AN: 840072

Other (OTH) AF: 0.00478 AC: 220 AN: 46010

GnomAD4 genome AF: 0.0173 AC: 1938 AN: 112071 Hom.: 35 Cov.: 23 AF XY: 0.0154 AC XY: 528 AN XY: 34233

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: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6067

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.000225 AC: 12 AN: 53220

Other (OTH) AF: 0.0144 AC: 22 AN: 1530

Alfa AF: 0.00565 Hom.: 300

Bravo AF: 0.0214

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.0602 AC: 231

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00591 AC: 718

EpiCase AF: 0.0000546

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.5
DANN	Benign	0.68
DEOGEN2	Benign	0.055	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.033
Sift	Benign	0.28	T
Sift4G	Benign	0.59	T
Polyphen		0.014	B
Vest4		0.034
MVP		0.53
MPC		0.56
ClinPred		0.0071	T
GERP RS		3.3
Varity_R		0.064
gMVP		0.098
Mutation Taster		=100/0	polymorphism (auto)

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: rs61746390; hg19: chrX-41555770;