2-164493133-C-T

Variant names:

• chr2-164493133-C-T
• NM_004490.3:c.1526G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004490.3(GRB14):​c.1526G>A​(p.Arg509Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRB14 NM_004490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

GRB14 (HGNC:4565): (growth factor receptor bound protein 14) The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor signaling. This gene may play a role in signaling pathways that regulate growth and metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22469252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRB14	NM_004490.3	c.1526G>A	p.Arg509Lys	missense_variant	Exon 14 of 14	ENST00000263915.8	NP_004481.2
GRB14	NM_001303422.2	c.1265G>A	p.Arg422Lys	missense_variant	Exon 13 of 13		NP_001290351.1
GRB14	XM_047444013.1	c.926G>A	p.Arg309Lys	missense_variant	Exon 13 of 13		XP_047299969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRB14	ENST00000263915.8	c.1526G>A	p.Arg509Lys	missense_variant	Exon 14 of 14	1	NM_004490.3	ENSP00000263915.3
GRB14	ENST00000696453.2	c.1265G>A	p.Arg422Lys	missense_variant	Exon 13 of 13			ENSP00000512640.1
GRB14	ENST00000488342.5	n.1662G>A		non_coding_transcript_exon_variant	Exon 14 of 14	5
GRB14	ENST00000497306.1	n.95G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1526G>A (p.R509K) alteration is located in exon 14 (coding exon 14) of the GRB14 gene. This alteration results from a G to A substitution at nucleotide position 1526, causing the arginine (R) at amino acid position 509 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.075	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.48		Gain of methylation at R509 (P = 0.0116);
MVP		0.56
MPC		0.058
ClinPred		0.41	T
GERP RS		3.7
Varity_R		0.64
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-165349643;