3-14506824-G-A

Position:

• chr3-14506824-G-A

Variant summary

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

The NM_001080423.4(GRIP2):​c.2375C>T​(p.Thr792Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GRIP2 NM_001080423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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=0.372282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIP2	NM_001080423.4	c.2375C>T	p.Thr792Ile	missense_variant	19/24	ENST00000621039.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIP2	ENST00000621039.5	c.2375C>T	p.Thr792Ile	missense_variant	19/24	1	NM_001080423.4	P2
GRIP2	ENST00000619221.4	c.2666C>T	p.Thr889Ile	missense_variant	20/25	5
GRIP2	ENST00000637182.1	c.2390C>T	p.Thr797Ile	missense_variant	19/24	5		A1
GRIP2	ENST00000430219.2	c.752C>T	p.Thr251Ile	missense_variant, NMD_transcript_variant	7/12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450828 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 24, 2023

The c.2666C>T (p.T889I) alteration is located in exon 20 (coding exon 20) of the GRIP2 gene. This alteration results from a C to T substitution at nucleotide position 2666, causing the threonine (T) at amino acid position 889 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.3
DANN	Benign	0.76
DEOGEN2	Benign	0.020	T;.;.
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.22	T;T;T
MetaRNN	Benign	0.37	T;T;T
MutationAssessor	Benign	0.85	L;.;.
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.42	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.12
MVP		0.69
GERP RS		1.1
Varity_R		0.048
gMVP		0.18

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: chr3-14548332;