dbSNP rs78631453: GRIN2A:p.Thr141Met (chr16-9938544-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001134407.3(GRIN2A):c.422C>T(p.Thr141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,603,046 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. T141K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.87

Publications

16 publications found

Variant links:

Genes affected

GRIN2A (HGNC:4585): (glutamate ionotropic receptor NMDA type subunit 2A) This gene encodes a member of the glutamate-gated ion channel protein family. The encoded protein is an N-methyl-D-aspartate (NMDA) receptor subunit. NMDA receptors are both ligand-gated and voltage-dependent, and are involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. These receptors are permeable to calcium ions, and activation results in a calcium influx into post-synaptic cells, which results in the activation of several signaling cascades. Disruption of this gene is associated with focal epilepsy and speech disorder with or without cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

GRIN2A Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Landau-Kleffner syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
continuous spikes and waves during sleep
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
rolandic epilepsy-speech dyspraxia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

GRIN2A 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=0.008182764).

BP6

Variant 16-9938544-G-A is Benign according to our data. Variant chr16-9938544-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 205638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000926 (141/152314) while in subpopulation NFE AF = 0.00159 (108/68022). AF 95% confidence interval is 0.00135. 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 Homozygotes in GnomAdExome4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134407.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2A	NM_001134407.3	MANE Select	c.422C>T	p.Thr141Met	missense	Exon 3 of 13	NP_001127879.1	Q12879-1
GRIN2A	NM_000833.5		c.422C>T	p.Thr141Met	missense	Exon 4 of 14	NP_000824.1	Q12879-1
GRIN2A	NM_001134408.2		c.422C>T	p.Thr141Met	missense	Exon 3 of 14	NP_001127880.1	Q12879-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.422C>T	p.Thr141Met	missense	Exon 3 of 13	ENSP00000332549.3	Q12879-1
GRIN2A	ENST00000396573.6	TSL:1	c.422C>T	p.Thr141Met	missense	Exon 4 of 14	ENSP00000379818.2	Q12879-1
GRIN2A	ENST00000562109.5	TSL:1	c.422C>T	p.Thr141Met	missense	Exon 3 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00111

AC:

260

AN:

235002

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.000200

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00363

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000367

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.000838

GnomAD4 exome

AF:

0.00156

AC:

2266

AN:

1450732

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1152

AN XY:

722104

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33470

American (AMR)

AF:

0.000581

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00367

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86238

European-Finnish (FIN)

AF:

0.000279

AC:

AN:

43064

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00175

AC:

1948

AN:

1111362

Other (OTH)

AF:

0.00114

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.000926

AC:

141

AN:

152314

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00163

Hom.:

Bravo

AF:

0.000963

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00154

AC:

ExAC

AF:

0.00104

AC:

126

EpiCase

AF:

0.00180

EpiControl

AF:

0.00166

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Landau-Kleffner syndrome (4)

not provided (4)

not specified (3)

GRIN2A-related complex neurodevelopmental disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.31

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

2.9

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.87

REVEL

Benign

0.18

Sift

Benign

0.21

Sift4G

Benign

0.29

Polyphen

0.016

Vest4

0.23

MVP

0.64

MPC

0.65

ClinPred

0.0050

GERP RS

1.6

Varity_R

0.032

gMVP

0.61

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over