Genetic Variant NM_002086.5:c.*1081G>A (chr17-75319287-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002086.5(GRB2):c.*1081G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 150,120 control chromosomes in the GnomAD database, including 31,773 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 31627 hom., cov: 25)

Exomes 𝑓: 0.82 ( 146 hom. )

Consequence

GRB2
NM_002086.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.597

Publications

38 publications found

Variant links:

Genes affected

GRB2 (HGNC:4566): (growth factor receptor bound protein 2) The protein encoded by this gene binds the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the Sem5 gene of C.elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GRB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRB2	NM_002086.5 link	c.*1081G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000316804.10	NP_002077.1
GRB2	NM_203506.3 link	c.*1081G>A		3_prime_UTR_variant	Exon 5 of 5		NP_987102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRB2	ENST00000316804.10 link	c.*1081G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_002086.5	ENSP00000339007.4

Frequencies

GnomAD3 genomes

AF:

0.608

AC:

90958

AN:

149578

Hom.:

31637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.243

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.687

Gnomad ASJ

AF:

0.568

Gnomad EAS

AF:

0.845

Gnomad SAS

AF:

0.670

Gnomad FIN

AF:

0.833

Gnomad MID

AF:

0.529

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.595

GnomAD4 exome

AF:

0.817

AC:

356

AN:

436

Hom.:

146

Cov.:

AF XY:

0.824

AC XY:

216

AN XY:

262

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.815

AC:

347

AN:

426

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AF:

0.833

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

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:

0.608

AC:

90947

AN:

149684

Hom.:

31627

Cov.:

AF XY:

0.615

AC XY:

44898

AN XY:

73000

show subpopulations

African (AFR)

AF:

0.243

AC:

9821

AN:

40452

American (AMR)

AF:

0.687

AC:

10320

AN:

15022

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

1963

AN:

3454

East Asian (EAS)

AF:

0.845

AC:

4318

AN:

5110

South Asian (SAS)

AF:

0.670

AC:

3167

AN:

4728

European-Finnish (FIN)

AF:

0.833

AC:

8336

AN:

10002

Middle Eastern (MID)

AF:

0.514

AC:

149

AN:

290

European-Non Finnish (NFE)

AF:

0.753

AC:

50945

AN:

67658

Other (OTH)

AF:

0.594

AC:

1225

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

1354

2708

4061

5415

6769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

730

1460

2190

2920

3650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.703

Hom.:

68083

Bravo

AF:

0.582

Asia WGS

AF:

0.672

AC:

2336

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over