19-48398414-C-A

Variant names:

• chr19-48398414-C-A
• rs2147434074
• NM_000836.4:c.22C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000836.4(GRIN2D):​c.22C>A​(p.Arg8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000537 in 1,118,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.107
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11247456).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.22C>A	p.Arg8Ser	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.22C>A	p.Arg8Ser	missense	Exon 3 of 14	ENSP00000263269.2	O15399
	GRIN2D	ENST00000911262.1		c.22C>A	p.Arg8Ser	missense	Exon 2 of 13	ENSP00000581321.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150592 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000517 AC: 5 AN: 967512 Hom.: 0 Cov.: 28 AF XY: 0.00000439 AC XY: 2 AN XY: 456000

African (AFR) AF: 0.00 AC: 0 AN: 18966

American (AMR) AF: 0.00 AC: 0 AN: 4616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9618

East Asian (EAS) AF: 0.00 AC: 0 AN: 16032

South Asian (SAS) AF: 0.00 AC: 0 AN: 19068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2342

European-Non Finnish (NFE) AF: 0.00000589 AC: 5 AN: 848644

Other (OTH) AF: 0.00 AC: 0 AN: 35286

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150698 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73640

African (AFR) AF: 0.00 AC: 0 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9974

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67516

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.11
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.052
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.042	D
Polyphen		0.17	B
Vest4		0.19
MutPred		0.38		Loss of MoRF binding (P = 0.0033)
MVP		0.46
ClinPred		0.46	T
GERP RS		-0.74
Varity_R		0.12
gMVP		0.33
Mutation Taster		=66/34	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: rs2147434074; hg19: chr19-48901671; COSMIC: COSV54382581;