19-48398426-G-A

Variant names:

• chr19-48398426-G-A
• rs1970668670
• NM_000836.4:c.34G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000836.4(GRIN2D):​c.34G>A​(p.Gly12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19451892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4	c.34G>A	p.Gly12Ser	missense_variant	Exon 3 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2	c.34G>A	p.Gly12Ser	missense_variant	Exon 1 of 12		XP_011525174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2D	ENST00000263269.4	c.34G>A	p.Gly12Ser	missense_variant	Exon 3 of 14	1	NM_000836.4	ENSP00000263269.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 969974 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 457618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the GRIN2D gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRIN2D protein function. This variant has not been reported in the literature in individuals affected with GRIN2D-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the GRIN2D protein (p.Gly12Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.058
Sift	Uncertain	0.026	D
Sift4G	Benign	0.15	T
Polyphen		0.74	P
Vest4		0.21
MutPred		0.16		Gain of phosphorylation at G12 (P = 0.007);
MVP		0.44
ClinPred		0.57	D
GERP RS		2.8
Varity_R		0.083
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs1970668670; hg19: chr19-48901683;