11-83874469-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001142699.3(DLG2):c.1516G>A(p.Ala506Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,601,074 control chromosomes in the GnomAD database, including 6 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 0.00092 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (4 hom.)
• Consequence: DLG2 NM_001142699.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.449

Genes affected

DLG2 (HGNC:2901): (discs large MAGUK scaffold protein 2) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. The encoded protein forms a heterodimer with a related family member that may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described, but their full-length nature is not known. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005573094).
• BP6: Variant 11-83874469-C-T is Benign according to our data. Variant chr11-83874469-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3038904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG2	NM_001142699.3	c.1516G>A	p.Ala506Thr	missense_variant	16/28	ENST00000376104.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG2	ENST00000376104.7	c.1516G>A	p.Ala506Thr	missense_variant	16/28	1	NM_001142699.3

Frequencies

GnomAD3 genomes AF: 0.000842 AC: 128 AN: 152068 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000232 AC: 57 AN: 245416 Hom.: 0 AF XY: 0.000195 AC XY: 26 AN XY: 133358

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.0000883

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000347

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 211 AN: 1448888 Hom.: 4 Cov.: 30 AF XY: 0.000125 AC XY: 90 AN XY: 720646

Gnomad4 AFR exome AF: 0.00295

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00215

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000453

Gnomad4 OTH exome AF: 0.000335

GnomAD4 genome AF: 0.000920 AC: 140 AN: 152186 Hom.: 2 Cov.: 31 AF XY: 0.000954 AC XY: 71 AN XY: 74428

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000945

ESP6500AA AF: 0.00314 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000323 AC: 39

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DLG2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	21
Dann	Benign	0.86
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.54	N;N;.;.;N;N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.29	T;T;.;.;T;T;T;T;T;T
Sift4G	Benign	0.36	T;T;.;.;T;T;T;T;T;T
Polyphen		0.0030, 0.0010, 0.0, 0.059	.;B;.;.;B;B;B;B;B;B
Vest4		0.22
MVP		0.30
MPC		0.64
ClinPred		0.0073	T
GERP RS		0.95
Varity_R		0.042
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs190715807; hg19: chr11-83585512; COSMIC: COSV99718525;