rs13277

Variant names:

• chr12-66392311-G-C
• rs13277
• NM_001366722.1:c.2461C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-66392311-G-C
• chr12-66392311-G-T

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: 7.63
• Publications: 26 publications found

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]

GRIP1 Gene-Disease associations (from GenCC):

• Fraser syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Fraser syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.2461C>G	p.Gln821Glu	missense_variant	Exon 19 of 25	ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.2461C>G	p.Gln821Glu	missense_variant	Exon 19 of 25	5	NM_001366722.1	ENSP00000352780.4

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

GnomAD2 exomes AF: 0.951 AC: 237058 AN: 249228 AF XY: 0.962

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 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

African (AFR) AF: 0.628 AC: 20724 AN: 32978

American (AMR) AF: 0.864 AC: 38590 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 25848 AN: 25966

East Asian (EAS) AF: 0.901 AC: 35658 AN: 39576

South Asian (SAS) AF: 0.993 AC: 85095 AN: 85710

European-Finnish (FIN) AF: 1.00 AC: 53404 AN: 53410

Middle Eastern (MID) AF: 0.978 AC: 5594 AN: 5722

European-Non Finnish (NFE) AF: 0.999 AC: 1086647 AN: 1087638

Other (OTH) AF: 0.967 AC: 57484 AN: 59472

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

African (AFR) AF: 0.636 AC: 26366 AN: 41470

American (AMR) AF: 0.870 AC: 13308 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3454 AN: 3472

East Asian (EAS) AF: 0.937 AC: 4832 AN: 5158

South Asian (SAS) AF: 0.990 AC: 4780 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10625 AN: 10626

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67904 AN: 68036

Other (OTH) AF: 0.915 AC: 1934 AN: 2114

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1 Benign:3

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 3 Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.35	.;T;T;T;.
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
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PhyloP100		7.6
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13277; hg19: chr12-66786091; COSMIC: COSV107266243; COSMIC: COSV107266243;