3-14507593-G-A

Position:

• chr3-14507593-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001080423.4(GRIP2):​c.2186C>T​(p.Thr729Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRIP2 NM_001080423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP2	NM_001080423.4	c.2186C>T	p.Thr729Ile	missense_variant	18/24	ENST00000621039.5	NP_001073892.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP2	ENST00000621039.5	c.2186C>T	p.Thr729Ile	missense_variant	18/24	1	NM_001080423.4	ENSP00000478352	P2
GRIP2	ENST00000619221.4	c.2477C>T	p.Thr826Ile	missense_variant	19/25	5		ENSP00000480660
GRIP2	ENST00000637182.1	c.2201C>T	p.Thr734Ile	missense_variant	18/24	5		ENSP00000490949	A1
GRIP2	ENST00000430219.2	c.563C>T	p.Thr188Ile	missense_variant, NMD_transcript_variant	6/12	2		ENSP00000481670

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 02, 2024

The c.2477C>T (p.T826I) alteration is located in exon 19 (coding exon 19) of the GRIP2 gene. This alteration results from a C to T substitution at nucleotide position 2477, causing the threonine (T) at amino acid position 826 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	0.30
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.087	T;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Pathogenic	0.76	D;D;D
MutationAssessor	Benign	0.86	L;.;.
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.12	T;T;.
Polyphen		0.65	P;.;.
Vest4		0.42
MVP		0.73
GERP RS		4.2
Varity_R		0.18
gMVP		0.60

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: rs1693966180; hg19: chr3-14549101;