19-48443247-T-A

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.3321T>A(p.Asp1107Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,460,980 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

GRIN2D
NM_000836.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.277

Publications

1 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=0.004858345).

BP6

Variant 19-48443247-T-A is Benign according to our data. Variant chr19-48443247-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 377345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000129 (19/147286) while in subpopulation AMR AF = 0.000802 (12/14960). AF 95% confidence interval is 0.000462. There are 1 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4 link	c.3321T>A	p.Asp1107Glu	missense_variant	Exon 14 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2 link	c.3321T>A	p.Asp1107Glu	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.3321T>A	p.Asp1107Glu	missense_variant	Exon 14 of 14	1	NM_000836.4	ENSP00000263269.2		O15399

Frequencies

GnomAD3 genomes

AF:

0.000129

AC:

AN:

147164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000803

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:

0.0000904

Gnomad OTH

AF:

0.000497

GnomAD2 exomes

AF:

0.000416

AC:

AN:

139544

AF XY:

0.000391

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000781

Gnomad OTH exome

AF:

0.000599

GnomAD4 exome

AF:

0.0000731

AC:

AN:

1313694

Hom.:

Cov.:

AF XY:

0.0000735

AC XY:

AN XY:

652820

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26664

American (AMR)

AF:

0.00162

AC:

AN:

32686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21298

East Asian (EAS)

AF:

0.00

AC:

AN:

27492

South Asian (SAS)

AF:

0.00

AC:

AN:

76574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4230

European-Non Finnish (NFE)

AF:

0.0000365

AC:

AN:

1040722

Other (OTH)

AF:

0.0000949

AC:

AN:

52684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000129

AC:

AN:

147286

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

71834

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40490

American (AMR)

AF:

0.000802

AC:

AN:

14960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

4800

South Asian (SAS)

AF:

0.00

AC:

AN:

4666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0000904

AC:

AN:

66374

Other (OTH)

AF:

0.000491

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

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:

0.00

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.000225

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.098

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.40

M_CAP

Benign

0.061

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.28

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.74

REVEL

Benign

0.019

Sift

Uncertain

0.0060

Sift4G

Benign

1.0

Polyphen

0.23

Vest4

0.058

MutPred

0.21

Gain of sheet (P = 0.0166);

MVP

0.49

ClinPred

0.016

GERP RS

0.58

Varity_R

0.11

gMVP

0.087

Mutation Taster

=92/8

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