12-66515609-C-T

Variant names:

• chr12-66515609-C-T
• rs12316942
• NM_001366722.1:c.724+10G>A

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.724+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,609,018 control chromosomes in the GnomAD database, including 328,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35396 hom., cov: 31)
  • Exomes 𝑓: 0.63 (292970 hom.)
• Consequence: GRIP1 NM_001366722.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0320
• 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=-0.9).
• BP6: Variant 12-66515609-C-T is Benign according to our data. Variant chr12-66515609-C-T is described in ClinVar as Benign. ClinVar VariationId is 261413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366722.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIP1	NM_001366722.1	MANE Select	c.724+10G>A		intron	N/A	NP_001353651.1
	GRIP1	NM_001379345.1		c.802+10G>A		intron	N/A	NP_001366274.1
	GRIP1	NM_001439322.1		c.727+10G>A		intron	N/A	NP_001426251.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIP1	ENST00000359742.9	TSL:5 MANE Select	c.724+10G>A		intron	N/A	ENSP00000352780.4
	GRIP1	ENST00000398016.7	TSL:1	c.724+10G>A		intron	N/A	ENSP00000381098.3
	GRIP1	ENST00000536215.5	TSL:1	c.556+10G>A		intron	N/A	ENSP00000446011.1

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102876 AN: 151884 Hom.: 35363 Cov.: 31

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.721

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.668

GnomAD2 exomes AF: 0.647 AC: 161390 AN: 249430 AF XY: 0.650

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.628

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.648

GnomAD4 exome AF: 0.632 AC: 920881 AN: 1457016 Hom.: 292970 Cov.: 34 AF XY: 0.635 AC XY: 460648 AN XY: 725196

African (AFR) AF: 0.808 AC: 26994 AN: 33390

American (AMR) AF: 0.633 AC: 28305 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 16994 AN: 26076

East Asian (EAS) AF: 0.676 AC: 26819 AN: 39670

South Asian (SAS) AF: 0.748 AC: 64451 AN: 86142

European-Finnish (FIN) AF: 0.581 AC: 31010 AN: 53394

Middle Eastern (MID) AF: 0.707 AC: 4067 AN: 5754

European-Non Finnish (NFE) AF: 0.617 AC: 683300 AN: 1107674

Other (OTH) AF: 0.647 AC: 38941 AN: 60210

GnomAD4 genome AF: 0.677 AC: 102968 AN: 152002 Hom.: 35396 Cov.: 31 AF XY: 0.678 AC XY: 50382 AN XY: 74276

African (AFR) AF: 0.801 AC: 33216 AN: 41484

American (AMR) AF: 0.675 AC: 10294 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2270 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3355 AN: 5152

South Asian (SAS) AF: 0.747 AC: 3602 AN: 4820

European-Finnish (FIN) AF: 0.575 AC: 6067 AN: 10556

Middle Eastern (MID) AF: 0.707 AC: 205 AN: 290

European-Non Finnish (NFE) AF: 0.617 AC: 41917 AN: 67952

Other (OTH) AF: 0.669 AC: 1411 AN: 2108

Alfa AF: 0.644 Hom.: 53516

Bravo AF: 0.685

Asia WGS AF: 0.712 AC: 2480 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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.27
PhyloP100		-0.032
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12316942; hg19: chr12-66909389;