11-83874444-A-G

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.1541T>C(p.Leu514Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000872 in 1,601,302 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (6 hom.)
• Consequence: DLG2 NM_001142699.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.95

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=0.008063883).
• BP6: Variant 11-83874444-A-G is Benign according to our data. Variant chr11-83874444-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 252537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG2	NM_001142699.3	c.1541T>C	p.Leu514Pro	missense_variant	16/28	ENST00000376104.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG2	ENST00000376104.7	c.1541T>C	p.Leu514Pro	missense_variant	16/28	1	NM_001142699.3

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00101 AC: 249 AN: 245464 Hom.: 1 AF XY: 0.00132 AC XY: 176 AN XY: 133312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000693

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.000894 AC: 1295 AN: 1448984 Hom.: 6 Cov.: 30 AF XY: 0.00105 AC XY: 760 AN XY: 720608

Gnomad4 AFR exome AF: 0.000331

Gnomad4 AMR exome AF: 0.000521

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000648

Gnomad4 OTH exome AF: 0.000888

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152318 Hom.: 0 Cov.: 31 AF XY: 0.000765 AC XY: 57 AN XY: 74488

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000736 Hom.: 1

Bravo AF: 0.000468

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000729 AC: 6

ExAC AF: 0.00118 AC: 143

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

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 18, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Benign	0.0049
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.0081	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.12	N;N;.;.;N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.15	T;T;.;.;T;T;T;T;T;D
Sift4G	Benign	0.26	T;T;.;.;T;T;T;T;T;T
Polyphen		0.52, 0.32, 0.97, 0.072, 0.10, 0.26, 0.0030	.;P;.;.;B;D;B;B;B;B
Vest4		0.75
MVP		0.89
MPC		2.0
ClinPred		0.046	T
GERP RS		5.6
Varity_R		0.22
gMVP		0.42

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: rs201235627; hg19: chr11-83585487;