chr12-66420707-C-A

Variant names:

• chr12-66420707-C-A
• rs7397862
• NM_001366722.1:c.1838+13G>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.1838+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,429,348 control chromosomes in the GnomAD database, including 253,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21439 hom., cov: 31)
  • Exomes 𝑓: 0.60 (232256 hom.)
• Consequence: GRIP1 NM_001366722.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.268
• Publications: 10 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 (BayesDel_noAF=-0.84).
• BP6: Variant 12-66420707-C-A is Benign according to our data. Variant chr12-66420707-C-A is described in ClinVar as Benign. ClinVar VariationId is 261409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.1838+13G>T		intron_variant	Intron 15 of 24	ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.1838+13G>T		intron_variant	Intron 15 of 24	5	NM_001366722.1	ENSP00000352780.4

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76414 AN: 151842 Hom.: 21430 Cov.: 31

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.534

GnomAD2 exomes AF: 0.565 AC: 140688 AN: 249078 AF XY: 0.574

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.596 AC: 761429 AN: 1277388 Hom.: 232256 Cov.: 19 AF XY: 0.598 AC XY: 385800 AN XY: 645368

African (AFR) AF: 0.237 AC: 7245 AN: 30566

American (AMR) AF: 0.530 AC: 23538 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 15400 AN: 24966

East Asian (EAS) AF: 0.317 AC: 12358 AN: 38942

South Asian (SAS) AF: 0.573 AC: 47281 AN: 82576

European-Finnish (FIN) AF: 0.651 AC: 34616 AN: 53182

Middle Eastern (MID) AF: 0.564 AC: 3074 AN: 5450

European-Non Finnish (NFE) AF: 0.622 AC: 586934 AN: 943004

Other (OTH) AF: 0.571 AC: 30983 AN: 54284

GnomAD4 genome AF: 0.503 AC: 76453 AN: 151960 Hom.: 21439 Cov.: 31 AF XY: 0.504 AC XY: 37437 AN XY: 74242

African (AFR) AF: 0.251 AC: 10380 AN: 41434

American (AMR) AF: 0.508 AC: 7754 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2135 AN: 3470

East Asian (EAS) AF: 0.328 AC: 1691 AN: 5152

South Asian (SAS) AF: 0.560 AC: 2695 AN: 4816

European-Finnish (FIN) AF: 0.652 AC: 6872 AN: 10542

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42960 AN: 67960

Other (OTH) AF: 0.535 AC: 1133 AN: 2116

Alfa AF: 0.570 Hom.: 5285

Bravo AF: 0.479

Asia WGS AF: 0.435 AC: 1514 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Fraser syndrome 1 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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 12, 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.26
PhyloP100		-0.27
Mutation Taster		=100/0	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: rs7397862; hg19: chr12-66814487; COSMIC: COSV54024696;