NM_000836.4:c.2041A>C

Variant names:

• chr19-48419764-A-C
• rs1555893359
• NM_000836.4:c.2041A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000836.4(GRIN2D):​c.2041A>C​(p.Met681Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4	c.2041A>C	p.Met681Leu	missense_variant	Exon 10 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2	c.2041A>C	p.Met681Leu	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.2041A>C	p.Met681Leu	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 20, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.2041A>C (p.M681L) alteration is located in exon 9 (coding exon 8) of the GRIN2D gene. This alteration results from a A to C substitution at nucleotide position 2041, causing the methionine (M) at amino acid position 681 to be replaced by a leucine (L). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GRIN2D c.2041A>C alteration was not observed, with coverage at this position. An alteration at the same codon has been observed in affected individuals:_x000D_ _x000D_ An alteration at the same codon with a different amino acid substitution, c.2043G>A (p.M681I), was reported de novo in a patient with developmental delay, epilepsy, autistic features, and a movement disorder (Tsuchida, 2018) The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.M681 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.M681 amino acid is located in the M3 transmembrane domain of GluN2D. The M3 segment of each subunit of the tetrameric receptor plays a critical role in channel gating. The p.M681 amino acid residue lies immediately adjacent to the highly conserved SYTANLAAF motif (amino acids 672-680), which is a critical determinant of channel gating in glutamate receptors (Yuan, 2005). Several alterations within the M3 ‘SYTANLAAF’ motif in multiple glutamate receptor subunits have been shown to lead to constitutively open channels and/or cause neurodegeneration in rodents (Zuo, 1997; Kashiwagi, 2002; Sobolevsky, 2007; Chang, 2008). Structural modeling of the p.M681L variant performed in house at Ambry Genetics was inconclusive; no clear steric effects are predicted to be introduced from a methionine to leucine change at this position. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.M681L alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Benign	0.15	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.93	P
Vest4		0.64
MutPred		0.59		Loss of sheet (P = 0.0457);
MVP		0.69
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.42
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555893359; hg19: chr19-48923021;