rs4542691

Positions:

• chr17-75330884-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002086.5(GRB2):​c.176+1816A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 152,044 control chromosomes in the GnomAD database, including 31,928 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 0.60 (31928 hom., cov: 30)
• Consequence: GRB2 NM_002086.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRB2	NM_002086.5	c.176+1816A>G		intron_variant		ENST00000316804.10	NP_002077.1
GRB2	NM_203506.3	c.176+1816A>G		intron_variant			NP_987102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRB2	ENST00000316804.10	c.176+1816A>G		intron_variant		1	NM_002086.5	ENSP00000339007	P1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91376 AN: 151926 Hom.: 31941 Cov.: 30

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.590

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.601 AC: 91368 AN: 152044 Hom.: 31928 Cov.: 30 AF XY: 0.610 AC XY: 45296 AN XY: 74310

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.567

Gnomad4 EAS AF: 0.866

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.832

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.587

Alfa AF: 0.715 Hom.: 52481

Bravo AF: 0.576

Asia WGS AF: 0.676 AC: 2352 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.072
DANN	Benign	0.38

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: rs4542691; hg19: chr17-73326965;