rs2240158

Variant names:

• chr19-1005231-C-T
• rs2240158
• NM_138690.3:c.1730C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138690.3(GRIN3B):​c.1730C>T​(p.Thr577Met) variant causes a missense change. The variant allele was found at a frequency of 0.382 in 1,613,224 control chromosomes in the GnomAD database, including 120,816 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12967 hom., cov: 33)
  • Exomes 𝑓: 0.38 (107849 hom.)
• Consequence: GRIN3B NM_138690.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.14
• Publications: 55 publications found

Genes affected

GRIN3B (HGNC:16768): (glutamate ionotropic receptor NMDA type subunit 3B) The protein encoded by this gene is a subunit of an N-methyl-D-aspartate (NMDA) receptor. The encoded protein is found primarily in motor neurons, where it forms a heterotetramer with GRIN1 to create an excitatory glycine receptor. Variations in this gene have been proposed to be linked to schizophrenia. [provided by RefSeq, Nov 2015]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050599575).
• BP6: Variant 19-1005231-C-T is Benign according to our data. Variant chr19-1005231-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN3B	NM_138690.3	c.1730C>T	p.Thr577Met	missense_variant	Exon 3 of 9	ENST00000234389.3	NP_619635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN3B	ENST00000234389.3	c.1730C>T	p.Thr577Met	missense_variant	Exon 3 of 9	1	NM_138690.3	ENSP00000234389.3
GRIN3B	ENST00000588335.1	n.480C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61560 AN: 151988 Hom.: 12959 Cov.: 33

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.365 AC: 91276 AN: 250132 AF XY: 0.363

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.161

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.380 AC: 555390 AN: 1461118 Hom.: 107849 Cov.: 56 AF XY: 0.379 AC XY: 275239 AN XY: 726914

African (AFR) AF: 0.512 AC: 17125 AN: 33476

American (AMR) AF: 0.309 AC: 13827 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9259 AN: 26118

East Asian (EAS) AF: 0.170 AC: 6729 AN: 39690

South Asian (SAS) AF: 0.335 AC: 28858 AN: 86254

European-Finnish (FIN) AF: 0.438 AC: 23166 AN: 52888

Middle Eastern (MID) AF: 0.357 AC: 2062 AN: 5768

European-Non Finnish (NFE) AF: 0.389 AC: 432193 AN: 1111862

Other (OTH) AF: 0.367 AC: 22171 AN: 60380

GnomAD4 genome AF: 0.405 AC: 61601 AN: 152106 Hom.: 12967 Cov.: 33 AF XY: 0.402 AC XY: 29917 AN XY: 74352

African (AFR) AF: 0.508 AC: 21082 AN: 41490

American (AMR) AF: 0.303 AC: 4627 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1198 AN: 3470

East Asian (EAS) AF: 0.168 AC: 869 AN: 5166

South Asian (SAS) AF: 0.328 AC: 1580 AN: 4814

European-Finnish (FIN) AF: 0.434 AC: 4592 AN: 10586

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.391 AC: 26591 AN: 67980

Other (OTH) AF: 0.365 AC: 768 AN: 2106

Alfa AF: 0.388 Hom.: 32574

Bravo AF: 0.400

TwinsUK AF: 0.391 AC: 1449

ALSPAC AF: 0.395 AC: 1521

ESP6500AA AF: 0.506 AC: 2228

ESP6500EA AF: 0.387 AC: 3324

ExAC AF: 0.369 AC: 44740

Asia WGS AF: 0.272 AC: 949 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.383

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24814139) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.9	N
PhyloP100		4.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	3.8	N
REVEL	Benign	0.095
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.036	B
Vest4		0.073
MPC		0.12
ClinPred		0.0056	T
GERP RS		4.5
Varity_R		0.068
gMVP		0.75
Mutation Taster		=96/4	polymorphism (auto)

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: rs2240158; hg19: chr19-1005230; COSMIC: COSV52258512; COSMIC: COSV52258512;