rs12600908

Positions:

• chr17-75332293-G-A

Variant summary

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

The NM_002086.5(GRB2):​c.176+407C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0961 in 152,178 control chromosomes in the GnomAD database, including 929 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 0.096 (929 hom., cov: 32)
• Consequence: GRB2 NM_002086.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.280

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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRB2	NM_002086.5	c.176+407C>T		intron_variant		ENST00000316804.10
GRB2	NM_203506.3	c.176+407C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRB2	ENST00000316804.10	c.176+407C>T		intron_variant		1	NM_002086.5	P1

Frequencies

GnomAD3 genomes AF: 0.0960 AC: 14604 AN: 152060 Hom.: 922 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0906

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.0961 AC: 14619 AN: 152178 Hom.: 929 Cov.: 32 AF XY: 0.0966 AC XY: 7183 AN XY: 74384

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.0904

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.0422

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0967 Hom.: 137

Bravo AF: 0.0882

Asia WGS AF: 0.154 AC: 534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.88
DANN	Benign	0.81

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: rs12600908; hg19: chr17-73328374;