22-39968118-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004810.4(GRAP2):c.536G>A(p.Arg179Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00899 in 1,608,518 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (104 hom.)
• Consequence: GRAP2 NM_004810.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.00

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049968064).
• BP6: Variant 22-39968118-G-A is Benign according to our data. Variant chr22-39968118-G-A is described in ClinVar as [Benign]. Clinvar id is 708853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRAP2	NM_004810.4	c.536G>A	p.Arg179Gln	missense_variant	6/8	ENST00000344138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRAP2	ENST00000344138.9	c.536G>A	p.Arg179Gln	missense_variant	6/8	1	NM_004810.4	P1
GRAP2	ENST00000407075.3	c.536G>A	p.Arg179Gln	missense_variant	5/7	1		P1
GRAP2	ENST00000481263.1	n.186G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00671 AC: 1021 AN: 152120 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00632

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00901

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00877 AC: 2076 AN: 236692 Hom.: 19 AF XY: 0.00951 AC XY: 1217 AN XY: 127984

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.0000573

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00974

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00923 AC: 13440 AN: 1456280 Hom.: 104 Cov.: 33 AF XY: 0.00960 AC XY: 6947 AN XY: 723988

Gnomad4 AFR exome AF: 0.00204

Gnomad4 AMR exome AF: 0.00446

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.00713

Gnomad4 NFE exome AF: 0.00913

Gnomad4 OTH exome AF: 0.00999

GnomAD4 genome AF: 0.00672 AC: 1023 AN: 152238 Hom.: 3 Cov.: 31 AF XY: 0.00671 AC XY: 499 AN XY: 74416

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00632

Gnomad4 NFE AF: 0.00901

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00655 Hom.: 2

Bravo AF: 0.00643

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00784 AC: 952

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	0.067
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.58	D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.18
Sift	Benign	0.036	D;D
Sift4G	Benign	0.27	T;T
Polyphen		0.34	B;B
Vest4		0.40
MVP		0.80
MPC		0.76
ClinPred		0.022	T
GERP RS		5.4
Varity_R		0.069
gMVP		0.24

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: rs61752259; hg19: chr22-40364122; COSMIC: COSV105905998; COSMIC: COSV105905998;