3-14517196-A-C

Position:

• chr3-14517196-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080423.4(GRIP2):​c.1174T>G​(p.Phe392Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: GRIP2 NM_001080423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

Genes affected

GRIP2 (HGNC:23841): (glutamate receptor interacting protein 2) Predicted to enable protein C-terminus binding activity. Predicted to be involved in several processes, including neurotransmitter receptor transport, endosome to postsynaptic membrane; positive regulation of AMPA glutamate receptor clustering; and positive regulation of excitatory postsynaptic potential. Predicted to act upstream of or within Notch signaling pathway; artery smooth muscle contraction; and positive regulation of blood pressure. Predicted to be located in cytoplasm; dendritic shaft; and neuron spine. Predicted to be active in glutamatergic synapse and postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36833626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP2	NM_001080423.4	c.1174T>G	p.Phe392Val	missense_variant	11/24	ENST00000621039.5	NP_001073892.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP2	ENST00000621039.5	c.1174T>G	p.Phe392Val	missense_variant	11/24	1	NM_001080423.4	ENSP00000478352	P2
GRIP2	ENST00000619221.4	c.1465T>G	p.Phe489Val	missense_variant	12/25	5		ENSP00000480660
GRIP2	ENST00000637182.1	c.1189T>G	p.Phe397Val	missense_variant	11/24	5		ENSP00000490949	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.1465T>G (p.F489V) alteration is located in exon 12 (coding exon 12) of the GRIP2 gene. This alteration results from a T to G substitution at nucleotide position 1465, causing the phenylalanine (F) at amino acid position 489 to be replaced by a valine (V). 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	0.16
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Benign	0.053	T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.37	T;T;T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.17	T;T;.
Polyphen		0.76	P;.;.
Vest4		0.50
MVP		0.68
GERP RS		4.4
Varity_R		0.34
gMVP		0.39

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: chr3-14558704;