9-137156765-G-C

Variant names:

• chr9-137156765-G-C
• rs141473515
• NM_007327.4:c.768G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_007327.4(GRIN1):​c.768G>C​(p.Gly256Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,589,422 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00082 (12 hom.)
• Consequence: GRIN1 NM_007327.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.658
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), 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: Ambry Genetics, G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-137156765-G-C is Benign according to our data. Variant chr9-137156765-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211112.
• BP7: Synonymous conserved (PhyloP=0.658 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000787 (120/152394) while in subpopulation EAS AF = 0.0218 (113/5192). AF 95% confidence interval is 0.0185. There are 2 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.768G>C	p.Gly256Gly	synonymous	Exon 5 of 20	NP_015566.1	Q05586-1
	GRIN1	NM_001437330.1		c.831G>C	p.Gly277Gly	synonymous	Exon 6 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.831G>C	p.Gly277Gly	synonymous	Exon 6 of 21	NP_001172019.1	Q05586-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.768G>C	p.Gly256Gly	synonymous	Exon 5 of 20	ENSP00000360616.3	Q05586-1
	GRIN1	ENST00000371553.8	TSL:1	c.831G>C	p.Gly277Gly	synonymous	Exon 6 of 21	ENSP00000360608.3	Q05586-6
	GRIN1	ENST00000371560.5	TSL:1	c.831G>C	p.Gly277Gly	synonymous	Exon 6 of 20	ENSP00000360615.3	Q05586-7

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152276 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00197 AC: 405 AN: 205114 AF XY: 0.00187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000655

Gnomad ASJ exome AF: 0.000330

Gnomad EAS exome AF: 0.0258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000766

GnomAD4 exome AF: 0.000816 AC: 1172 AN: 1437028 Hom.: 12 Cov.: 34 AF XY: 0.000813 AC XY: 580 AN XY: 713026

African (AFR) AF: 0.00 AC: 0 AN: 32922

American (AMR) AF: 0.0000961 AC: 4 AN: 41612

Ashkenazi Jewish (ASJ) AF: 0.000468 AC: 12 AN: 25642

East Asian (EAS) AF: 0.0279 AC: 1060 AN: 38046

South Asian (SAS) AF: 0.000181 AC: 15 AN: 82970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49220

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5738

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1101408

Other (OTH) AF: 0.00114 AC: 68 AN: 59470

GnomAD4 genome AF: 0.000787 AC: 120 AN: 152394 Hom.: 2 Cov.: 34 AF XY: 0.000939 AC XY: 70 AN XY: 74524

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism

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: rs141473515; hg19: chr9-140051217; COSMIC: COSV59293767; COSMIC: COSV59293767;