3-49510575-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004393.6(DAG1):c.41C>G(p.Ser14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,856 control chromosomes in the GnomAD database, including 800,027 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.98 ( 72546 hom., cov: 27)

Exomes 𝑓: 1.0 ( 727481 hom. )

Consequence

DAG1
NM_004393.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.73

Publications

36 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: G2P, Genomics England PanelApp, Orphanet
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2135001E-6).

BP6

Variant 3-49510575-C-G is Benign according to our data. Variant chr3-49510575-C-G is described in ClinVar as Benign. ClinVar VariationId is 226558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6 link	c.41C>G	p.Ser14Trp	missense_variant	Exon 2 of 3	ENST00000308775.7	NP_004384.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000308775.7 link	c.41C>G	p.Ser14Trp	missense_variant	Exon 2 of 3	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes

AF:

0.976

AC:

148289

AN:

151908

Hom.:

72491

Cov.:

show subpopulations

Gnomad AFR

AF:

0.916

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.992

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.987

GnomAD2 exomes

AF:

0.994

AC:

249425

AN:

251000

AF XY:

0.995

show subpopulations

Gnomad AFR exome

AF:

0.914

Gnomad AMR exome

AF:

0.996

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.998

AC:

1458269

AN:

1461830

Hom.:

727481

Cov.:

AF XY:

0.998

AC XY:

725686

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.914

AC:

30612

AN:

33480

American (AMR)

AF:

0.996

AC:

44524

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26136

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39700

AN:

39700

South Asian (SAS)

AF:

1.00

AC:

86232

AN:

86256

European-Finnish (FIN)

AF:

1.00

AC:

53369

AN:

53370

Middle Eastern (MID)

AF:

0.998

AC:

5747

AN:

5758

European-Non Finnish (NFE)

AF:

1.00

AC:

1111864

AN:

1112010

Other (OTH)

AF:

0.995

AC:

60085

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

214

428

642

856

1070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21668

43336

65004

86672

108340

<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:

0.976

AC:

148403

AN:

152026

Hom.:

72546

Cov.:

AF XY:

0.976

AC XY:

72563

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.917

AC:

37956

AN:

41412

American (AMR)

AF:

0.992

AC:

15132

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5169

AN:

5172

South Asian (SAS)

AF:

1.00

AC:

4798

AN:

4800

European-Finnish (FIN)

AF:

1.00

AC:

10606

AN:

10606

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

67983

AN:

68002

Other (OTH)

AF:

0.987

AC:

2081

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

165

330

494

659

824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.943

Hom.:

16724

Bravo

AF:

0.973

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.921

AC:

4059

ESP6500EA

AF:

1.00

AC:

8596

ExAC

AF:

0.992

AC:

120479

Asia WGS

AF:

0.995

AC:

3461

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.41C) is the minor allele. This all ele (C) has been identified in 0.05% (4/8600) of European American chromosomes a nd 7.9% (347/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs2131107). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2P

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.34

T;T;T;T;T;T;T;.;.;.;.;.;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.090

T;T;.;.;.;.;.;T;T;T;T;T;T;.

MetaRNN

Benign

0.0000012

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.4

N;.;N;N;N;N;N;.;.;.;.;.;.;.

PhyloP100

1.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.090

N;N;N;N;N;N;N;N;N;N;N;N;N;D

REVEL

Benign

0.20

Sift

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T;T;T;.

Polyphen

0.0

B;.;B;B;B;B;B;.;.;.;.;.;.;.

Vest4

0.10

MPC

0.37

ClinPred

0.0070

GERP RS

4.7

Varity_R

0.027

gMVP

0.42

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over