rs1019385

Variant names:

• chr12-13981909-C-A
• rs1019385
• NM_001413992.1:c.-683+7G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-13981909-C-A
• chr12-13981909-C-G
• chr12-13981909-C-T

Variant summary

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

The NM_001413992.1(GRIN2B):​c.-683+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 153,050 control chromosomes in the GnomAD database, including 13,168 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 0.38 (13015 hom., cov: 29)
  • Exomes 𝑓: 0.45 (153 hom.)
• Consequence: GRIN2B NM_001413992.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.835
• Publications: 51 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_001413992.1	c.-683+7G>T		splice_region_variant, intron_variant	Intron 1 of 14		NP_001400921.1
GRIN2B	NM_001413993.1	c.-254+7G>T		splice_region_variant, intron_variant	Intron 1 of 3		NP_001400922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000630791.3	c.-683+7G>T		splice_region_variant, intron_variant	Intron 1 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000627535.2	c.-448+7G>T		splice_region_variant, intron_variant	Intron 1 of 2	5		ENSP00000486411.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57319 AN: 151406 Hom.: 13018 Cov.: 29

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.411

GnomAD4 exome AF: 0.450 AC: 689 AN: 1532 Hom.: 153 Cov.: 0 AF XY: 0.467 AC XY: 387 AN XY: 828

African (AFR) AF: 0.107 AC: 3 AN: 28

American (AMR) AF: 0.714 AC: 10 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 14 AN: 20

East Asian (EAS) AF: 0.534 AC: 31 AN: 58

South Asian (SAS) AF: 0.667 AC: 8 AN: 12

European-Finnish (FIN) AF: 0.434 AC: 324 AN: 746

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.449 AC: 273 AN: 608

Other (OTH) AF: 0.575 AC: 23 AN: 40

GnomAD4 genome AF: 0.378 AC: 57320 AN: 151518 Hom.: 13015 Cov.: 29 AF XY: 0.384 AC XY: 28391 AN XY: 73980

African (AFR) AF: 0.116 AC: 4819 AN: 41418

American (AMR) AF: 0.566 AC: 8622 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1803 AN: 3466

East Asian (EAS) AF: 0.562 AC: 2846 AN: 5062

South Asian (SAS) AF: 0.552 AC: 2634 AN: 4776

European-Finnish (FIN) AF: 0.417 AC: 4388 AN: 10514

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30885 AN: 67730

Other (OTH) AF: 0.412 AC: 866 AN: 2104

Alfa AF: 0.424 Hom.: 21696

Bravo AF: 0.378

Asia WGS AF: 0.515 AC: 1795 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		-0.83
PromoterAI		0.053	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1019385; hg19: chr12-14134843; COSMIC: COSV74205295;