rs13277

Positions:

• chr12-66392311-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366722.1(GRIP1):​c.2461C>G​(p.Gln821Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,587,370 control chromosomes in the GnomAD database, including 755,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (61226 hom., cov: 32)
  • Exomes 𝑓: 0.98 (694649 hom.)
• Consequence: GRIP1 NM_001366722.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.63

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.574098E-7).
• BP6: Variant 12-66392311-G-C is Benign according to our data. Variant chr12-66392311-G-C is described in ClinVar as [Benign]. Clinvar id is 261410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-66392311-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIP1	NM_001366722.1	c.2461C>G	p.Gln821Glu	missense_variant	19/25	ENST00000359742.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIP1	ENST00000359742.9	c.2461C>G	p.Gln821Glu	missense_variant	19/25	5	NM_001366722.1	P1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134343 AN: 152090 Hom.: 61211 Cov.: 32

Gnomad AFR AF: 0.636

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.990

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.914

GnomAD3 exomes AF: 0.951 AC: 237058 AN: 249228 Hom.: 114010 AF XY: 0.962 AC XY: 130121 AN XY: 135230

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.861

Gnomad ASJ exome AF: 0.995

Gnomad EAS exome AF: 0.949

Gnomad SAS exome AF: 0.993

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.969

GnomAD4 exome AF: 0.982 AC: 1409044 AN: 1435162 Hom.: 694649 Cov.: 26 AF XY: 0.984 AC XY: 704320 AN XY: 715744

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.864

Gnomad4 ASJ exome AF: 0.995

Gnomad4 EAS exome AF: 0.901

Gnomad4 SAS exome AF: 0.993

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.967

GnomAD4 genome AF: 0.883 AC: 134402 AN: 152208 Hom.: 61226 Cov.: 32 AF XY: 0.885 AC XY: 65872 AN XY: 74416

Gnomad4 AFR AF: 0.636

Gnomad4 AMR AF: 0.870

Gnomad4 ASJ AF: 0.995

Gnomad4 EAS AF: 0.937

Gnomad4 SAS AF: 0.990

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.915

Alfa AF: 0.980 Hom.: 55370

Bravo AF: 0.862

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 0.999 AC: 3851

ESP6500AA AF: 0.669 AC: 2717

ESP6500EA AF: 0.997 AC: 8312

ExAC AF: 0.949 AC: 114719

Asia WGS AF: 0.940 AC: 3270 AN: 3478

EpiCase AF: 0.997

EpiControl AF: 0.998

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fraser syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Fraser syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.70
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.70	T;T;T;T;T
MetaRNN	Benign	8.6e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0000017	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.33	T;T;T;T;T
Sift4G	Benign	1.0	T;T;.;T;.
Polyphen		0.49	P;P;P;.;.
Vest4		0.28
MPC		0.32
ClinPred		0.056	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.41

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: rs13277; hg19: chr12-66786091;