3-14493679-G-A

Position:

• chr3-14493679-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.3118C>T​(p.Pro1040Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,451,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 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: 0.0000069 (0 hom.)
• Consequence: GRIP2 NM_001080423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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=0.26868886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP2	NM_001080423.4	c.3118C>T	p.Pro1040Ser	missense_variant	24/24	ENST00000621039.5	NP_001073892.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP2	ENST00000621039.5	c.3118C>T	p.Pro1040Ser	missense_variant	24/24	1	NM_001080423.4	ENSP00000478352	P2
GRIP2	ENST00000619221.4	c.3409C>T	p.Pro1137Ser	missense_variant	25/25	5		ENSP00000480660
GRIP2	ENST00000637182.1	c.3133C>T	p.Pro1045Ser	missense_variant	24/24	5		ENSP00000490949	A1
GRIP2	ENST00000430219.2	c.*778C>T		3_prime_UTR_variant, NMD_transcript_variant	12/12	2		ENSP00000481670

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451494 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721074

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: 0.00000813

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

Mar 01, 2024

The c.3409C>T (p.P1137S) alteration is located in exon 25 (coding exon 25) of the GRIP2 gene. This alteration results from a C to T substitution at nucleotide position 3409, causing the proline (P) at amino acid position 1137 to be replaced by a serine (S). 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	0.092
BayesDel_addAF	Benign	-0.0054	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.032	T;.;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.27	T;T;T
MutationAssessor	Benign	1.9	M;.;.
PrimateAI	Benign	0.45	T
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.30	B;.;.
Vest4		0.20
MVP		0.72
GERP RS		2.5
Varity_R		0.12
gMVP		0.33

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: chr3-14535187;