dbSNP rs78190191: DLG1:p.Arg786Gln (chr3-197065292-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001366207.1(DLG1):c.2357G>A(p.Arg786Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,606,026 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.015 ( 20 hom., cov: 31)

Exomes 𝑓: 0.021 ( 382 hom. )

Consequence

DLG1
NM_001366207.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.04

Publications

9 publications found

Variant links:

Genes affected

DLG1 (HGNC:2900): (discs large MAGUK scaffold protein 1) This gene encodes a multi-domain scaffolding protein that is required for normal development. This protein may have a role in septate junction formation, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. A multitude of transcript variants deriving from alternative splicing and the use of multiple alternate promoter have been observed, including some splice variants that may be specific to brain and other tissues. An upstream uORF may regulate translation at some splice variants of this gene. [provided by RefSeq, Sep 2018]

DLG1 Gene-Disease associations (from GenCC):

Brugada syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

DLG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067587793).

BP6

Variant 3-197065292-C-T is Benign according to our data. Variant chr3-197065292-C-T is described in ClinVar as Benign. ClinVar VariationId is 3041899.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0147 (2235/151924) while in subpopulation NFE AF = 0.0238 (1616/67966). AF 95% confidence interval is 0.0228. There are 20 homozygotes in GnomAd4. There are 1106 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366207.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLG1	NM_001366207.1	MANE Select	c.2357G>A	p.Arg786Gln	missense	Exon 22 of 25	NP_001353136.1	Q12959-4
DLG1	NM_004087.2		c.2456G>A	p.Arg819Gln	missense	Exon 23 of 26	NP_004078.2	Q12959-2
DLG1	NM_001366214.1		c.2453G>A	p.Arg818Gln	missense	Exon 23 of 26	NP_001353143.1	A0A590UJD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLG1	ENST00000667157.1	MANE Select	c.2357G>A	p.Arg786Gln	missense	Exon 22 of 25	ENSP00000499414.1	Q12959-4
DLG1	ENST00000346964.6	TSL:1	c.2456G>A	p.Arg819Gln	missense	Exon 23 of 26	ENSP00000345731.2	Q12959-2
DLG1	ENST00000419354.5	TSL:1	c.2390G>A	p.Arg797Gln	missense	Exon 23 of 26	ENSP00000407531.1	Q12959-1

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2235

AN:

151806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00389

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00526

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00748

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0238

Gnomad OTH

AF:

0.00912

GnomAD2 exomes

AF:

0.0165

AC:

4032

AN:

244010

AF XY:

0.0168

show subpopulations

Gnomad AFR exome

AF:

0.00341

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0251

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0207

AC:

30160

AN:

1454102

Hom.:

382

Cov.:

AF XY:

0.0205

AC XY:

14830

AN XY:

723296

show subpopulations

African (AFR)

AF:

0.00275

AC:

AN:

33074

American (AMR)

AF:

0.00571

AC:

245

AN:

42920

Ashkenazi Jewish (ASJ)

AF:

0.00570

AC:

147

AN:

25806

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39508

South Asian (SAS)

AF:

0.00755

AC:

637

AN:

84422

European-Finnish (FIN)

AF:

0.0290

AC:

1532

AN:

52904

Middle Eastern (MID)

AF:

0.00488

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0238

AC:

26395

AN:

1109620

Other (OTH)

AF:

0.0180

AC:

1083

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1392

2784

4177

5569

6961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

938

1876

2814

3752

4690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0147

AC:

2235

AN:

151924

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1106

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.00388

AC:

161

AN:

41460

American (AMR)

AF:

0.00525

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00749

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0291

AC:

306

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0238

AC:

1616

AN:

67966

Other (OTH)

AF:

0.00902

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0208

Hom.:

134

Bravo

AF:

0.0124

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0170

AC:

2061

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

DLG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

2.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.11

Sift

Benign

0.10

Sift4G

Benign

0.21

Polyphen

0.99

Vest4

0.57

MPC

0.74

ClinPred

0.039

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.87

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over