19-48398396-C-T

Variant names:

• chr19-48398396-C-T
• rs982702259
• NM_000836.4:c.4C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000836.4(GRIN2D):​c.4C>T​(p.Arg2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 967,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 0 publications found

Genes affected

GRIN2D (HGNC:4588): (glutamate ionotropic receptor NMDA type subunit 2D) N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. NMDA channel has been shown to be involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. NMDA receptor channels are heteromers composed of the key receptor subunit NMDAR1 (GRIN1) and 1 or more of the 4 NMDAR2 subunits: NMDAR2A (GRIN2A), NMDAR2B (GRIN2B), NMDAR2C (GRIN2C), and NMDAR2D (GRIN2D). [provided by RefSeq, Mar 2010]

GRIN2D Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 46

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23110229).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000836.4. 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
	GRIN2D	NM_000836.4	MANE Select	c.4C>T	p.Arg2Cys	missense	Exon 3 of 14	NP_000827.2	O15399

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2D	ENST00000263269.4	TSL:1 MANE Select	c.4C>T	p.Arg2Cys	missense	Exon 3 of 14	ENSP00000263269.2	O15399
	GRIN2D	ENST00000911262.1		c.4C>T	p.Arg2Cys	missense	Exon 2 of 13	ENSP00000581321.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 967722 Hom.: 0 Cov.: 28 AF XY: 0.00000219 AC XY: 1 AN XY: 455722

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18986

American (AMR) AF: 0.00 AC: 0 AN: 4538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9646

East Asian (EAS) AF: 0.00 AC: 0 AN: 16312

South Asian (SAS) AF: 0.00 AC: 0 AN: 18684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2332

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 848810

Other (OTH) AF: 0.00 AC: 0 AN: 35342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.41	N
REVEL	Benign	0.042
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.017	B
Vest4		0.29
MutPred		0.37		Loss of MoRF binding (P = 2e-04)
MVP		0.38
ClinPred		0.47	T
GERP RS		1.1
Varity_R		0.14
gMVP		0.33
Mutation Taster		=82/18	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: rs982702259; hg19: chr19-48901653;