11-83484201-A-G

Variant names:

• chr11-83484201-A-G
• rs774058599
• NM_001142699.3:c.2221T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142699.3(DLG2):​c.2221T>C​(p.Phe741Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F741V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLG2 NM_001142699.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98
• Publications: 0 publications found

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]

DLG2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• delayed puberty, self-limited

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27041805).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142699.3. 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
	DLG2	NM_001142699.3	MANE Select	c.2221T>C	p.Phe741Leu	missense	Exon 22 of 28	NP_001136171.1	Q15700-2
	DLG2	NM_001206769.2		c.2023T>C	p.Phe675Leu	missense	Exon 16 of 22	NP_001193698.1	Q15700-4
	DLG2	NM_001377966.1		c.2023T>C	p.Phe675Leu	missense	Exon 16 of 22	NP_001364895.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG2	ENST00000376104.7	TSL:1 MANE Select	c.2221T>C	p.Phe741Leu	missense	Exon 22 of 28	ENSP00000365272.2	Q15700-2
	DLG2	ENST00000398309.6	TSL:1	c.1906T>C	p.Phe636Leu	missense	Exon 17 of 23	ENSP00000381355.2	Q15700-1
	DLG2	ENST00000532653.5	TSL:1	c.1879-903T>C		intron	N/A	ENSP00000435849.1	B7Z2T4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N
PhyloP100		6.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Benign	0.38	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.45
MutPred		0.29		Gain of loop (P = 0.0312)
MVP		0.77
MPC		0.86
ClinPred		0.76	D
GERP RS		5.2
PromoterAI		-0.0056	Neutral
Varity_R		0.20
gMVP		0.53
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs774058599; hg19: chr11-83195244;