chr12-66420707-C-A

Position:

• chr12-66420707-C-A

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.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

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 (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 id is 261409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-66420707-C-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.1838+13G>T		intron_variant		ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.1838+13G>T		intron_variant		5	NM_001366722.1	ENSP00000352780	P1

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

GnomAD3 exomes AF: 0.565 AC: 140688 AN: 249078 Hom.: 41435 AF XY: 0.574 AC XY: 77625 AN XY: 135162

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 SAS exome AF: 0.575

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

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.530

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.573

Gnomad4 FIN exome AF: 0.651

Gnomad4 NFE exome AF: 0.622

Gnomad4 OTH exome AF: 0.571

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

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.560

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.632

Gnomad4 OTH AF: 0.535

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fraser syndrome 1 Benign:2

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	- -

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 12, 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.26

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: rs7397862; hg19: chr12-66814487; COSMIC: COSV54024696;