12-66432560-T-G

Position:

• chr12-66432560-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001366722.1(GRIP1):​c.1756A>C​(p.Ile586Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00219 in 1,584,386 control chromosomes in the GnomAD database, including 5 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: GRIP1 NM_001366722.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 6.30

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013707876).
• BP6: Variant 12-66432560-T-G is Benign according to our data. Variant chr12-66432560-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265191.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr12-66432560-T-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.1756A>C	p.Ile586Leu	missense_variant	14/25	ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.1756A>C	p.Ile586Leu	missense_variant	14/25	5	NM_001366722.1	ENSP00000352780.4

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00128 AC: 318 AN: 248122 Hom.: 1 AF XY: 0.00134 AC XY: 180 AN XY: 134746

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00226 AC: 3243 AN: 1432058 Hom.: 5 Cov.: 26 AF XY: 0.00218 AC XY: 1555 AN XY: 714236

Gnomad4 AFR exome AF: 0.000456

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000549

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74484

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00155

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00159 AC: 13

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	GRIP1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	The I534L variant in the GRIP1 gene was reported previously using alternate nomenclature I586L in an individual with autism and was absent in 480 control individuals (Mejias et al., 2011). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports I534L was observed in 13/8166 alleles from individuals of European American background, indicating it may be a rare variant in this population. The I534L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. The I534L variant caused increased interaction, faster recycling, and increased surface distribution of glutamate receptor in live, transfected hippocampal neurons, suggesting gain-of-function (Mejias et al., 2011). We interpret I534L as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Fraser syndrome 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Jan 29, 2018	This is a 12 year old male with intellectual disability, autism spectrum disorder, mild hyptonia, hyperkinesis, and sleep problems. He has no history of seizures. This p.Ile534Leu variant is present in gnomAD non-Finnish European population at 0.22%. Computational prediction models are inconsistent. This patient does not have congenital anomalies that would be consistent with Fraser syndrome. This variant has been reported as a possible modifier of autism (Mejias, 2011) using alternate nomenclature (I586L). Whole exome sequencing identified a likely pathogenic, de novo variant in SCN2A and 1 additional variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: GRIP1 c.1600A>C (p.Ile534Leu) results in a conservative amino acid change located in the PDZ domain (IPR001478) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 248122 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in GRIP1 causing Cryptophthalmos Syndrome phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1600A>C has been reported in the literature in two heterozygous brothers affected with autism; it had been inherited from their unaffected mother (Mejias_2010). Experimental evidence provided by the authors demonstrated the variant was associated with altered interactions with glutamate receptors 2/3 in a yeast two-hybrid assay and faster recycling and increased surface distribution of GluA2 in rat neurons. This report does not provide unequivocal conclusions about association of the variant with Cryptophthalmos Syndrome. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign for Cryptophthalmos Syndrome. -

GRIP1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;T;T;T;.
Eigen	Benign	0.099
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	.;L;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.084	T;T;T;T;T
Sift4G	Benign	0.14	T;T;.;T;.
Polyphen		0.032	B;B;B;.;.
Vest4		0.62
MutPred		0.47		.;Gain of catalytic residue at S590 (P = 0);.;.;.;
MVP		0.58
MPC		0.80
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.35
gMVP		0.62

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: rs189438534; hg19: chr12-66826340;