16-9764645-C-G

Variant names:

• chr16-9764645-C-G
• rs61731465
• NM_001134407.3:c.2899G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134407.3(GRIN2A):​c.2899G>C​(p.Val967Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,614,128 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (61 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.869
• Publications: 16 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044463575).
• BP6: Variant 16-9764645-C-G is Benign according to our data. Variant chr16-9764645-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129195.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 = 0.00516 (785/152272) while in subpopulation NFE AF = 0.00822 (559/68018). AF 95% confidence interval is 0.00765. There are 2 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	NM_001134407.3	MANE Select	c.2899G>C	p.Val967Leu	missense	Exon 13 of 13	NP_001127879.1	Q12879-1
	GRIN2A	NM_000833.5		c.2899G>C	p.Val967Leu	missense	Exon 14 of 14	NP_000824.1	Q12879-1
	GRIN2A	NM_001134408.2		c.2899G>C	p.Val967Leu	missense	Exon 13 of 14	NP_001127880.1	Q12879-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.2899G>C	p.Val967Leu	missense	Exon 13 of 13	ENSP00000332549.3	Q12879-1
	GRIN2A	ENST00000396573.6	TSL:1	c.2899G>C	p.Val967Leu	missense	Exon 14 of 14	ENSP00000379818.2	Q12879-1
	GRIN2A	ENST00000562109.5	TSL:1	c.2899G>C	p.Val967Leu	missense	Exon 13 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152154 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00822

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00583 AC: 1466 AN: 251404 AF XY: 0.00622

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00753 AC: 11013 AN: 1461856 Hom.: 61 Cov.: 34 AF XY: 0.00745 AC XY: 5415 AN XY: 727232

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00398 AC: 178 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00769 AC: 663 AN: 86258

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53418

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00850 AC: 9449 AN: 1111980

Other (OTH) AF: 0.00593 AC: 358 AN: 60394

GnomAD4 genome AF: 0.00516 AC: 785 AN: 152272 Hom.: 2 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74456

African (AFR) AF: 0.00161 AC: 67 AN: 41548

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00768 AC: 37 AN: 4818

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00822 AC: 559 AN: 68018

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00641 Hom.: 2

Bravo AF: 0.00492

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00387 AC: 17

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00573 AC: 696

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00836

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Landau-Kleffner syndrome (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.51
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.060	N
PhyloP100		0.87
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.47		Loss of methylation at K972 (P = 0.0967)
MVP		0.17
MPC		0.25
ClinPred		0.0015	T
GERP RS		4.5
Varity_R		0.072
gMVP		0.31
Mutation Taster		=100/0	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: rs61731465; hg19: chr16-9858502; COSMIC: COSV105221349; COSMIC: COSV105221349;