rs571334598

Variant names:

• chr19-48442691-C-A
• rs571334598
• NM_000836.4:c.2765C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-48442691-C-A
• chr19-48442691-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000836.4(GRIN2D):​c.2765C>A​(p.Ala922Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,036,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A922V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: GRIN2D NM_000836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1149109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4	c.2765C>A	p.Ala922Glu	missense_variant	Exon 14 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2	c.2765C>A	p.Ala922Glu	missense_variant	Exon 12 of 12		XP_011525174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2D	ENST00000263269.4	c.2765C>A	p.Ala922Glu	missense_variant	Exon 14 of 14	1	NM_000836.4	ENSP00000263269.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000193 AC: 2 AN: 1036136 Hom.: 0 Cov.: 31 AF XY: 0.00000201 AC XY: 1 AN XY: 496376

⚠️ 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: 20408

American (AMR) AF: 0.00 AC: 0 AN: 6408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10940

East Asian (EAS) AF: 0.00 AC: 0 AN: 19624

South Asian (SAS) AF: 0.00 AC: 0 AN: 24994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2594

European-Non Finnish (NFE) AF: 0.00000224 AC: 2 AN: 892886

Other (OTH) AF: 0.00 AC: 0 AN: 39430

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2765C>A (p.A922E) alteration is located in exon 13 (coding exon 12) of the GRIN2D gene. This alteration results from a C to A substitution at nucleotide position 2765, causing the alanine (A) at amino acid position 922 to be replaced by a glutamic acid (E). 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	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.057
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.78	P
Vest4		0.15
MutPred		0.21		Gain of solvent accessibility (P = 0.0068);
MVP		0.27
ClinPred		0.13	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.18
gMVP		0.34
Mutation Taster		=91/9	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: rs571334598; hg19: chr19-48945948;