3-49510539-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004393.6(DAG1):c.5G>A(p.Arg2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DAG1
NM_004393.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.87

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22423178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6 link	c.5G>A	p.Arg2Lys	missense_variant	Exon 2 of 3	ENST00000308775.7	NP_004384.5	Q14118A0A024R2W4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000308775.7 link	c.5G>A	p.Arg2Lys	missense_variant	Exon 2 of 3	1	NM_004393.6	ENSP00000312435.2		Q14118

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460942

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5322

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Dec 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2 of the DAG1 protein (p.Arg2Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DAG1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

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

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.39

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

M_CAP

Benign

0.0073

MetaRNN

Benign

0.22

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

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

PhyloP100

2.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.16

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

REVEL

Benign

0.061

Sift

Benign

0.11

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

Sift4G

Benign

0.91

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

Polyphen

0.0

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

Vest4

0.066

MutPred

0.28

Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);Gain of glycosylation at S4 (P = 0.0069);

MVP

0.49

MPC

0.34

ClinPred

0.40

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.090

gMVP

0.56

Mutation Taster

=92/8

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over