rs397517433

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032119.4(ADGRV1):c.6676G>A(p.Glu2226Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000202 in 1,581,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.99

Publications

3 publications found

Variant links:

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ADGRV1 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2C
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 4
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ADGRV1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4005829).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.6676G>A	p.Glu2226Lys	missense_variant	Exon 30 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 link	c.6676G>A	p.Glu2226Lys	missense_variant	Exon 30 of 90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000501

AC:

AN:

199796

AF XY:

0.00000935

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1429528

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

708444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32980

American (AMR)

AF:

0.00

AC:

AN:

39646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25538

East Asian (EAS)

AF:

0.00

AC:

AN:

38808

South Asian (SAS)

AF:

0.00

AC:

AN:

82354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000256

AC:

AN:

1093426

Other (OTH)

AF:

0.0000169

AC:

AN:

59280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Glu2226Lys vari ant in GPR98 has not been previously identified by our laboratory and it has not been identified in large and broad African American and European American popul ations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) . Computational analyses (biochemical amino acid properties, conservation, Align GVGD, PolyPhen2, and SIFT) suggest that the Glu2226Lys variant may not impact th e protein, particularly with the Glu2226 amino acid not conserved in rat or lowe r species. However, this information is not predictive enough to rule out pathog enicity. In summary, the clinical significance of this variant cannot be determi ned with certainty; however based upon the reduced conservation, we would lean t owards a more likely benign role. -

Inborn genetic diseases

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.6676G>A (p.E2226K) alteration is located in exon 30 (coding exon 30) of the ADGRV1 gene. This alteration results from a G to A substitution at nucleotide position 6676, causing the glutamic acid (E) at amino acid position 2226 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Benign

-0.94

PhyloP100

5.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

.;N;.

REVEL

Benign

0.18

Sift

Benign

0.22

.;T;.

Sift4G

Benign

0.17

.;T;.

Polyphen

0.99

D;D;.

Vest4

0.84

MutPred

0.52

Gain of ubiquitination at E2226 (P = 0.03);Gain of ubiquitination at E2226 (P = 0.03);.;

MVP

0.69

MPC

0.20

ClinPred

0.94

GERP RS

5.4

Varity_R

0.46

gMVP

0.73

Mutation Taster

=89/11

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over