Genetic Variant DAG1:p.His752His (chr3-49532767-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004393.6(DAG1):c.2256C>T(p.His752His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,613,778 control chromosomes in the GnomAD database, including 75,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7134 hom., cov: 32)

Exomes 𝑓: 0.30 ( 68546 hom. )

Consequence

DAG1
NM_004393.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 1.80

Publications

39 publications found

Variant links:

Genes affected

DAG1 (HGNC:2666): (dystroglycan 1) This gene encodes dystroglycan, a central component of dystrophin-glycoprotein complex that links the extracellular matrix and the cytoskeleton in the skeletal muscle. The encoded preproprotein undergoes O- and N-glycosylation, and proteolytic processing to generate alpha and beta subunits. Certain mutations in this gene are known to cause distinct forms of muscular dystrophy. Alternative splicing results in multiple transcript variants, all encoding the same protein. [provided by RefSeq, Nov 2015]

DAG1 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2P
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
isolated asymptomatic elevation of creatine phosphokinase
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 3-49532767-C-T is Benign according to our data. Variant chr3-49532767-C-T is described in ClinVar as Benign. ClinVar VariationId is 31755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004393.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DAG1	NM_004393.6	MANE Select	c.2256C>T	p.His752His	synonymous	Exon 3 of 3	NP_004384.5	Q14118
DAG1	NM_001165928.4		c.2256C>T	p.His752His	synonymous	Exon 6 of 6	NP_001159400.3	Q14118
DAG1	NM_001177634.3		c.2256C>T	p.His752His	synonymous	Exon 6 of 6	NP_001171105.2	Q14118

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DAG1	ENST00000308775.7	TSL:1 MANE Select	c.2256C>T	p.His752His	synonymous	Exon 3 of 3	ENSP00000312435.2	Q14118
DAG1	ENST00000418588.6	TSL:3	c.2256C>T	p.His752His	synonymous	Exon 4 of 4	ENSP00000405859.2	Q14118
DAG1	ENST00000421560.6	TSL:4	c.2256C>T	p.His752His	synonymous	Exon 3 of 3	ENSP00000412067.2	Q14118

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44904

AN:

152022

Hom.:

7128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.0588

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.471

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.297

GnomAD2 exomes

AF:

0.279

AC:

69706

AN:

250230

AF XY:

0.282

show subpopulations

Gnomad AFR exome

AF:

0.287

Gnomad AMR exome

AF:

0.156

Gnomad ASJ exome

AF:

0.456

Gnomad EAS exome

AF:

0.0553

Gnomad FIN exome

AF:

0.465

Gnomad NFE exome

AF:

0.310

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.298

AC:

435877

AN:

1461638

Hom.:

68546

Cov.:

AF XY:

0.297

AC XY:

215892

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.289

AC:

9680

AN:

33478

American (AMR)

AF:

0.163

AC:

7297

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

11887

AN:

26136

East Asian (EAS)

AF:

0.0632

AC:

2508

AN:

39700

South Asian (SAS)

AF:

0.242

AC:

20865

AN:

86258

European-Finnish (FIN)

AF:

0.454

AC:

24159

AN:

53270

Middle Eastern (MID)

AF:

0.317

AC:

1830

AN:

5768

European-Non Finnish (NFE)

AF:

0.305

AC:

339432

AN:

1111928

Other (OTH)

AF:

0.302

AC:

18219

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

23024

46048

69072

92096

115120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10978

21956

32934

43912

54890

<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:

0.295

AC:

44933

AN:

152140

Hom.:

7134

Cov.:

AF XY:

0.298

AC XY:

22153

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.290

AC:

12019

AN:

41510

American (AMR)

AF:

0.218

AC:

3330

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

1601

AN:

3472

East Asian (EAS)

AF:

0.0591

AC:

306

AN:

5176

South Asian (SAS)

AF:

0.226

AC:

1089

AN:

4820

European-Finnish (FIN)

AF:

0.471

AC:

4994

AN:

10592

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.305

AC:

20698

AN:

67954

Other (OTH)

AF:

0.295

AC:

623

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1609

3218

4828

6437

8046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.308

Hom.:

4584

Bravo

AF:

0.275

Asia WGS

AF:

0.149

AC:

523

AN:

3478

EpiCase

AF:

0.314

EpiControl

AF:

0.308

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Autosomal recessive limb-girdle muscular dystrophy type 2P (2)

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P (1)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.6

(source)

DANN

Benign

0.51

PhyloP100

1.8

Mutation Taster

=98/2

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