19-48398420-C-A

Variant names:

• chr19-48398420-C-A
• rs1473663651
• NM_000836.4:c.28C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_000836.4(GRIN2D):​c.28C>A​(p.Pro10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,120,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0260
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16604358).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000133 (2/150474) while in subpopulation EAS AF = 0.000389 (2/5138). AF 95% confidence interval is 0.0000688. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.28C>A	p.Pro10Thr	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.28C>A	p.Pro10Thr	missense	Exon 3 of 14	ENSP00000263269.2	O15399
	GRIN2D	ENST00000911262.1		c.28C>A	p.Pro10Thr	missense	Exon 2 of 13	ENSP00000581321.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150366 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 969686 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 457324

African (AFR) AF: 0.00 AC: 0 AN: 19010

American (AMR) AF: 0.00 AC: 0 AN: 4774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9694

East Asian (EAS) AF: 0.0000620 AC: 1 AN: 16132

South Asian (SAS) AF: 0.00 AC: 0 AN: 19314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 849976

Other (OTH) AF: 0.00 AC: 0 AN: 35378

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150474 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73498

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67462

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.026
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.059
Sift	Benign	0.42	T
Sift4G	Benign	0.10	T
Polyphen		0.74	P
Vest4		0.25
MutPred		0.25		Gain of phosphorylation at P10 (P = 0.0106)
MVP		0.74
ClinPred		0.24	T
GERP RS		0.62
Varity_R		0.062
gMVP		0.37
Mutation Taster		=68/32	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: rs1473663651; hg19: chr19-48901677;