chr12-13754507-G-A

Position:

• chr12-13754507-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000834.5(GRIN2B):​c.412-592C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 152,306 control chromosomes in the GnomAD database, including 62 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 0.023 (62 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0231 (3519/152306) while in subpopulation SAS AF= 0.0457 (221/4834). AF 95% confidence interval is 0.0408. There are 62 homozygotes in gnomad4. There are 1785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3519 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.412-592C>T		intron_variant		ENST00000609686.4	NP_000825.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.412-592C>T		intron_variant		1	NM_000834.5	ENSP00000477455	P1
GRIN2B	ENST00000630791.2	c.412-592C>T		intron_variant		5		ENSP00000486677

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3521 AN: 152188 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0272

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0231 AC: 3519 AN: 152306 Hom.: 62 Cov.: 32 AF XY: 0.0240 AC XY: 1785 AN XY: 74474

Gnomad4 AFR AF: 0.00762

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0457

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0281 Hom.: 21

Bravo AF: 0.0226

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.78

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: rs1805554; hg19: chr12-13907441;