12-13561795-T-C

Variant names:

• chr12-13561795-T-C
• rs1805477
• NM_000834.5:c.*988A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000834.5(GRIN2B):​c.*988A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 152,696 control chromosomes in the GnomAD database, including 64,234 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.91 (64016 hom., cov: 32)
  • Exomes 𝑓: 1.0 (218 hom.)
• Consequence: GRIN2B NM_000834.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.196
• Publications: 7 publications found

Genes affected

GRIN2B (HGNC:4586): (glutamate ionotropic receptor NMDA type subunit 2B) This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]

GRIN2B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• developmental and epileptic encephalopathy, 27

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• intellectual disability, autosomal dominant 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000834.5. 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
	GRIN2B	NM_000834.5	MANE Select	c.*988A>G		3_prime_UTR	Exon 14 of 14	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.*988A>G		3_prime_UTR	Exon 15 of 15	NP_001400921.1	A0A8D9PHB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.*988A>G		3_prime_UTR	Exon 14 of 14	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.*988A>G		3_prime_UTR	Exon 15 of 15	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000637214.1	TSL:5	c.69+46808A>G		intron	N/A	ENSP00000489997.1	A0A1B0GU78

Frequencies

GnomAD3 genomes AF: 0.906 AC: 137773 AN: 152142 Hom.: 63980 Cov.: 32

Gnomad AFR AF: 0.672

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.936

GnomAD4 exome AF: 1.00 AC: 436 AN: 436 Hom.: 218 Cov.: 0 AF XY: 1.00 AC XY: 264 AN XY: 264

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 426 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 6 AN: 6

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.905 AC: 137859 AN: 152260 Hom.: 64016 Cov.: 32 AF XY: 0.909 AC XY: 67647 AN XY: 74450

African (AFR) AF: 0.672 AC: 27908 AN: 41500

American (AMR) AF: 0.962 AC: 14719 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3459 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5168 AN: 5168

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67969 AN: 68044

Other (OTH) AF: 0.937 AC: 1980 AN: 2114

Alfa AF: 0.919 Hom.: 4965

Bravo AF: 0.892

Asia WGS AF: 0.977 AC: 3399 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs1805477; hg19: chr12-13714729;