Genetic Variant NM_002086.5:c.78+20210G>A (chr17-75373341-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002086.5(GRB2):c.78+20210G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 152,122 control chromosomes in the GnomAD database, including 38,220 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 0.66 ( 38217 hom., cov: 32)

Exomes 𝑓: 1.0 ( 3 hom. )

Consequence

GRB2
NM_002086.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.913

Publications

33 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:

ENSG00000264853 (HGNC:):

ENSG00000264853 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002086.5. 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
	GRB2	NM_002086.5	MANE Select	c.78+20210G>A		intron	N/A	NP_002077.1	B0LPF3
	GRB2	NM_203506.3		c.78+20210G>A		intron	N/A	NP_987102.1	P62993-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRB2	ENST00000316804.10	TSL:1 MANE Select	c.78+20210G>A	intron	N/A	ENSP00000339007.4	P62993-1
GRB2	ENST00000392564.5	TSL:1	c.78+20210G>A	intron	N/A	ENSP00000376347.1	P62993-1
GRB2	ENST00000392563.5	TSL:1	c.78+20210G>A	intron	N/A	ENSP00000376346.1	P62993-2

Frequencies

GnomAD3 genomes

AF:

0.662

AC:

100552

AN:

151998

Hom.:

38228

Cov.:

show subpopulations

Gnomad AFR

AF:

0.257

Gnomad AMI

AF:

0.785

Gnomad AMR

AF:

0.739

Gnomad ASJ

AF:

0.714

Gnomad EAS

AF:

0.911

Gnomad SAS

AF:

0.735

Gnomad FIN

AF:

0.885

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.826

Gnomad OTH

AF:

0.670

GnomAD4 exome

AF:

1.00

AC:

AN:

Hom.:

Cov.:

AF XY:

1.00

AC XY:

AN XY:

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:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AC:

AN:

Age Distribution

Exome Hom

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:

0.661

AC:

100544

AN:

152116

Hom.:

38217

Cov.:

AF XY:

0.669

AC XY:

49756

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.257

AC:

10634

AN:

41446

American (AMR)

AF:

0.739

AC:

11285

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.714

AC:

2477

AN:

3468

East Asian (EAS)

AF:

0.911

AC:

4715

AN:

5178

South Asian (SAS)

AF:

0.735

AC:

3546

AN:

4826

European-Finnish (FIN)

AF:

0.885

AC:

9380

AN:

10598

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.826

AC:

56192

AN:

68008

Other (OTH)

AF:

0.669

AC:

1411

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1280

2560

3839

5119

6399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.776

Hom.:

202431

Bravo

AF:

0.633

Asia WGS

AF:

0.738

AC:

2568

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.61

(source)

DANN

Benign

0.76

PhyloP100

-0.91

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over