19-48442691-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000836.4(GRIN2D):c.2765C>T(p.Ala922Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,184,806 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A922E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 2 hom. )

Consequence

GRIN2D
NM_000836.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.32

Publications

0 publications found

Variant links:

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

GRIN2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069673657).

BP6

Variant 19-48442691-C-T is Benign according to our data. Variant chr19-48442691-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000895 (133/148668) while in subpopulation AFR AF = 0.00301 (124/41142). AF 95% confidence interval is 0.00258. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4 link	c.2765C>T	p.Ala922Val	missense_variant	Exon 14 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2 link	c.2765C>T	p.Ala922Val	missense_variant	Exon 12 of 12		XP_011525174.1	O15399

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2D	ENST00000263269.4 link	c.2765C>T	p.Ala922Val	missense_variant	Exon 14 of 14	1	NM_000836.4	ENSP00000263269.2		O15399

Frequencies

GnomAD3 genomes

AF:

0.000895

AC:

133

AN:

148558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000468

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:

0.0000300

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000729

AC:

AN:

2742

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00420

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000676

AC:

AN:

1036138

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

496378

show subpopulations

African (AFR)

AF:

0.00299

AC:

AN:

20408

American (AMR)

AF:

0.000312

AC:

AN:

6408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10940

East Asian (EAS)

AF:

0.00

AC:

AN:

19624

South Asian (SAS)

AF:

0.00

AC:

AN:

24994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2594

European-Non Finnish (NFE)

AF:

0.00000112

AC:

AN:

892888

Other (OTH)

AF:

0.000152

AC:

AN:

39430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000895

AC:

133

AN:

148668

Hom.:

Cov.:

AF XY:

0.000911

AC XY:

AN XY:

72484

show subpopulations

African (AFR)

AF:

0.00301

AC:

124

AN:

41142

American (AMR)

AF:

0.000467

AC:

AN:

14976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66630

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000783

Hom.:

Bravo

AF:

0.000967

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 31, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GRIN2D-related disorder

Benign:1

Apr 20, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.43

M_CAP

Benign

0.074

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

1.3

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.49

REVEL

Benign

0.059

Sift

Uncertain

0.019

Sift4G

Benign

0.45

Polyphen

0.62

Vest4

0.13

MVP

0.32

ClinPred

0.046

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.12

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over