rs181365280

Positions:

• chr12-66392445-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001366722.1(GRIP1):​c.2327G>A​(p.Gly776Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,614,116 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (1 hom.)
• Consequence: GRIP1 NM_001366722.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.03

Genes affected

GRIP1 (HGNC:18708): (glutamate receptor interacting protein 1) This gene encodes a member of the glutamate receptor interacting protein family. The encoded scaffold protein binds to and mediates the trafficking and membrane organization of a number of transmembrane proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13789913).
• BP6: Variant 12-66392445-C-T is Benign according to our data. Variant chr12-66392445-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435390.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.2327G>A	p.Gly776Glu	missense_variant	19/25	ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.2327G>A	p.Gly776Glu	missense_variant	19/25	5	NM_001366722.1	ENSP00000352780	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249442 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135328

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461840 Hom.: 1 Cov.: 35 AF XY: 0.0000385 AC XY: 28 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 14, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.2171G>A (p.G724E) alteration is located in exon 18 (coding exon 18) of the GRIP1 gene. This alteration results from a G to A substitution at nucleotide position 2171, causing the glycine (G) at amino acid position 724 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.23	.;T;T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;.;.;.
MutationTaster	Benign	0.70	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	N;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.40	T;T;.;T;.
Polyphen		0.0	B;B;B;.;.
Vest4		0.063
MVP		0.18
MPC		0.43
ClinPred		0.023	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs181365280; hg19: chr12-66786225;