12-66515609-C-T

Position:

• chr12-66515609-C-T

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.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

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=-0.9).
• BP6: Variant 12-66515609-C-T is Benign according to our data. Variant chr12-66515609-C-T is described in ClinVar as [Benign]. Clinvar id is 261413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-66515609-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.724+10G>A		intron_variant		ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.724+10G>A		intron_variant		5	NM_001366722.1	ENSP00000352780.4

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

GnomAD3 exomes AF: 0.647 AC: 161390 AN: 249430 Hom.: 52940 AF XY: 0.650 AC XY: 87970 AN XY: 135330

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 SAS exome AF: 0.749

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

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.652

Gnomad4 EAS exome AF: 0.676

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.617

Gnomad4 OTH exome AF: 0.647

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

Gnomad4 AFR AF: 0.801

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.617

Gnomad4 OTH AF: 0.669

Alfa AF: 0.639 Hom.: 43161

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

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

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	-0.90
CADD	Benign	0.30
DANN	Benign	0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs12316942; hg19: chr12-66909389;