19-48398462-T-A

Variant names:

• chr19-48398462-T-A
• rs1600967287
• NM_000836.4:c.70T>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000836.4(GRIN2D):​c.70T>A​(p.Cys24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000109 in 915,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0370
• 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=0.1312544).
• BP6: Variant 19-48398462-T-A is Benign according to our data. Variant chr19-48398462-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3042328.Status of the report is no_assertion_criteria_provided, 0 stars.

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.70T>A	p.Cys24Ser	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.70T>A	p.Cys24Ser	missense	Exon 3 of 14	ENSP00000263269.2	O15399
	GRIN2D	ENST00000911262.1		c.70T>A	p.Cys24Ser	missense	Exon 2 of 13	ENSP00000581321.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 915774 Hom.: 0 Cov.: 28 AF XY: 0.00000233 AC XY: 1 AN XY: 428596

⚠️ 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: 17706

American (AMR) AF: 0.00 AC: 0 AN: 3230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7888

East Asian (EAS) AF: 0.00 AC: 0 AN: 11398

South Asian (SAS) AF: 0.00 AC: 0 AN: 17970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2072

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 814656

Other (OTH) AF: 0.00 AC: 0 AN: 32214

⚠️ 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.: 30

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GRIN2D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.037
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.12	T
Polyphen		0.43	B
Vest4		0.31
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.33
ClinPred		0.35	T
GERP RS		1.8
Varity_R		0.23
gMVP		0.45
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: rs1600967287; hg19: chr19-48901719;