rs886040861

Variant names:

• chr19-48419722-G-A
• rs886040861
• NM_000836.4:c.1999G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000836.4(GRIN2D):​c.1999G>A​(p.Val667Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.93
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000836.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 19-48419722-G-A is Pathogenic according to our data. Variant chr19-48419722-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 267211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4	c.1999G>A	p.Val667Ile	missense_variant	Exon 10 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2	c.1999G>A	p.Val667Ile	missense_variant	Exon 8 of 12		XP_011525174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2D	ENST00000263269.4	c.1999G>A	p.Val667Ile	missense_variant	Exon 10 of 14	1	NM_000836.4	ENSP00000263269.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 46 Pathogenic:5

Jun 25, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2016

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 30, 2020

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.54		Loss of catalytic residue at V667 (P = 0.0064);
MVP		0.75
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.44
gMVP		0.81
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886040861; hg19: chr19-48922979;