Genetic Variant GRIN2D:p.Leu20Leu (chr19-48398452-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2BP4_ModerateBP6_ModerateBP7BS1

The NM_000836.4(GRIN2D):c.60G>A(p.Leu20Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 148,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GRIN2D
NM_000836.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 19-48398452-G-A is Benign according to our data. Variant chr19-48398452-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2998915.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.32 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000202 (3/148824) while in subpopulation AFR AF = 0.0000731 (3/41054). AF 95% confidence interval is 0.0000194. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2D	NM_000836.4 link	c.60G>A	p.Leu20Leu	synonymous_variant	Exon 3 of 14	ENST00000263269.4	NP_000827.2
GRIN2D	XM_011526872.2 link	c.60G>A	p.Leu20Leu	synonymous_variant	Exon 1 of 12		XP_011525174.1	O15399

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2D	ENST00000263269.4 link	c.60G>A	p.Leu20Leu	synonymous_variant	Exon 3 of 14	1	NM_000836.4	ENSP00000263269.2		O15399

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000731

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

946406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

445684

African (AFR)

AF:

0.00

AC:

AN:

18370

American (AMR)

AF:

0.00

AC:

AN:

4300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8876

East Asian (EAS)

AF:

0.00

AC:

AN:

13782

South Asian (SAS)

AF:

0.00

AC:

AN:

19376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

834602

Other (OTH)

AF:

0.00

AC:

AN:

33942

GnomAD4 genome

AF:

0.0000202

AC:

AN:

148824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72554

show subpopulations

African (AFR)

AF:

0.0000731

AC:

AN:

41054

American (AMR)

AF:

0.00

AC:

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66910

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

1.3

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over