chr22-39969459-G-A

Position:

chr22-39969459-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004810.4(GRAP2):c.739G>A(p.Gly247Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,042 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 45 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 39 hom. )

Consequence

GRAP2
NM_004810.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.17

Variant links:

Genes affected

GRAP2 (HGNC:4563): (GRB2 related adaptor protein 2) This gene encodes a member of the GRB2/Sem5/Drk family. This member is an adaptor-like protein involved in leukocyte-specific protein-tyrosine kinase signaling. Like its related family member, GRB2-related adaptor protein (GRAP), this protein contains an SH2 domain flanked by two SH3 domains. This protein interacts with other proteins, such as GRB2-associated binding protein 1 (GAB1) and the SLP-76 leukocyte protein (LCP2), through its SH3 domains. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

GRAP2 links:

GRAP2 (HGNC:):

GRAP2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026841164).

BP6

Variant 22-39969459-G-A is Benign according to our data. Variant chr22-39969459-G-A is described in ClinVar as [Benign]. Clinvar id is 711088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (2002/152276) while in subpopulation AFR AF= 0.0455 (1893/41560). AF 95% confidence interval is 0.0438. There are 45 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRAP2	NM_004810.4 linkuse as main transcript	c.739G>A	p.Gly247Ser	missense_variant	7/8	ENST00000344138.9	NP_004801.1	O75791-1Q6FI14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRAP2	ENST00000344138.9 linkuse as main transcript	c.739G>A	p.Gly247Ser	missense_variant	7/8	1	NM_004810.4	ENSP00000339186.4	O75791-1
GRAP2	ENST00000407075.3 linkuse as main transcript	c.739G>A	p.Gly247Ser	missense_variant	6/7	1		ENSP00000385607.3	O75791-1
GRAP2	ENST00000460449.1 linkuse as main transcript	n.85G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1999

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00439

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00322

AC:

811

AN:

251478

Hom.:

AF XY:

0.00239

AC XY:

325

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0440

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00136

AC:

1991

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

801

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0459

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.0131

AC:

2002

AN:

152276

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

946

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0455

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.0144

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0370

AC:

163

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00387

AC:

470

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.62

.;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.33

PROVEAN

Benign

0.34

N;N

REVEL

Benign

0.059

Sift

Benign

0.79

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.014

B;B

Vest4

0.056

MVP

0.54

MPC

0.39

ClinPred

0.00029

GERP RS

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.033

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over