rs6293

Variant names:

• chr9-137156786-A-G
• rs6293
• NM_007327.4:c.789A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007327.4(GRIN1):​c.789A>G​(p.Pro263Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,592,168 control chromosomes in the GnomAD database, including 75,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5439 hom., cov: 34)
  • Exomes 𝑓: 0.30 (70137 hom.)
• Consequence: GRIN1 NM_007327.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.37
• Publications: 23 publications found

Genes affected

GRIN1 (HGNC:4584): (glutamate ionotropic receptor NMDA type subunit 1) The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

GRIN1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• developmental and epileptic encephalopathy 101

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105376328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-137156786-A-G is Benign according to our data. Variant chr9-137156786-A-G is described in ClinVar as Benign. ClinVar VariationId is 129182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	NM_007327.4	MANE Select	c.789A>G	p.Pro263Pro	synonymous	Exon 5 of 20	NP_015566.1
	GRIN1	NM_001437330.1		c.852A>G	p.Pro284Pro	synonymous	Exon 6 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.852A>G	p.Pro284Pro	synonymous	Exon 6 of 21	NP_001172019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.789A>G	p.Pro263Pro	synonymous	Exon 5 of 20	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.852A>G	p.Pro284Pro	synonymous	Exon 6 of 21	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.852A>G	p.Pro284Pro	synonymous	Exon 6 of 20	ENSP00000360615.3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35756 AN: 152172 Hom.: 5438 Cov.: 34

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.217

GnomAD2 exomes AF: 0.261 AC: 55350 AN: 212100 AF XY: 0.265

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.00181

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.302 AC: 435155 AN: 1439878 Hom.: 70137 Cov.: 48 AF XY: 0.300 AC XY: 214453 AN XY: 714414

African (AFR) AF: 0.0550 AC: 1818 AN: 33044

American (AMR) AF: 0.199 AC: 8380 AN: 42172

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6767 AN: 25736

East Asian (EAS) AF: 0.00138 AC: 53 AN: 38472

South Asian (SAS) AF: 0.229 AC: 19187 AN: 83660

European-Finnish (FIN) AF: 0.411 AC: 20451 AN: 49780

Middle Eastern (MID) AF: 0.279 AC: 1601 AN: 5740

European-Non Finnish (NFE) AF: 0.328 AC: 360956 AN: 1101742

Other (OTH) AF: 0.268 AC: 15942 AN: 59532

GnomAD4 genome AF: 0.235 AC: 35758 AN: 152290 Hom.: 5439 Cov.: 34 AF XY: 0.237 AC XY: 17629 AN XY: 74452

African (AFR) AF: 0.0663 AC: 2757 AN: 41588

American (AMR) AF: 0.225 AC: 3438 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 890 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5178

South Asian (SAS) AF: 0.210 AC: 1013 AN: 4824

European-Finnish (FIN) AF: 0.403 AC: 4279 AN: 10606

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22428 AN: 67994

Other (OTH) AF: 0.215 AC: 454 AN: 2116

Alfa AF: 0.288 Hom.: 3902

Bravo AF: 0.213

Asia WGS AF: 0.0900 AC: 315 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.5
DANN	Benign	0.59
PhyloP100		-5.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6293; hg19: chr9-140051238; COSMIC: COSV59293251; COSMIC: COSV59293251;