rs2131107

Variant names:

• chr3-49510575-C-A
• rs2131107
• NM_004393.6:c.41C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-49510575-C-A
• chr3-49510575-C-G
• chr3-49510575-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004393.6(DAG1):​c.41C>A​(p.Ser14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S14S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 27)
• Consequence: DAG1 NM_004393.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.73
• Publications: 36 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-49510575-C-A is Pathogenic according to our data. Variant chr3-49510575-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1073860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6	c.41C>A	p.Ser14*	stop_gained	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	c.41C>A	p.Ser14*	stop_gained	Exon 2 of 3	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser14*) in the DAG1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DAG1-related disease. Loss-of-function variants in DAG1 are known to be pathogenic (PMID: 25934851). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		1.7
Vest4		0.76
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=5/195	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs2131107; hg19: chr3-49548008;