3-49510406-C-CT

Variant names:

• chr3-49510406-C-CT
• rs200455639
• ENST00000479935.1:n.192dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004393.6(DAG1):​c.-116-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 921,352 control chromosomes in the GnomAD database, including 34 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (32 hom.)
• Consequence: DAG1 NM_004393.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.648
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 3-49510406-C-CT is Benign according to our data. Variant chr3-49510406-C-CT is described in ClinVar as [Benign]. Clinvar id is 420471.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6	c.-116-4dupT		splice_region_variant, intron_variant	Intron 1 of 2	ENST00000308775.7	NP_004384.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000308775.7	c.-116-4dupT		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 812 AN: 151318 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00214

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00620

Gnomad ASJ AF: 0.00924

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00238

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00812

Gnomad OTH AF: 0.00674

GnomAD4 exome AF: 0.00887 AC: 6831 AN: 769918 Hom.: 32 Cov.: 11 AF XY: 0.00850 AC XY: 3464 AN XY: 407358

African (AFR) AF: 0.00285 AC: 57 AN: 20012

American (AMR) AF: 0.00555 AC: 221 AN: 39788

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 216 AN: 20762

East Asian (EAS) AF: 0.000221 AC: 8 AN: 36254

South Asian (SAS) AF: 0.00177 AC: 124 AN: 69998

European-Finnish (FIN) AF: 0.00448 AC: 170 AN: 37928

Middle Eastern (MID) AF: 0.00647 AC: 18 AN: 2780

European-Non Finnish (NFE) AF: 0.0112 AC: 5662 AN: 504782

Other (OTH) AF: 0.00944 AC: 355 AN: 37614

GnomAD4 genome AF: 0.00536 AC: 812 AN: 151434 Hom.: 2 Cov.: 32 AF XY: 0.00506 AC XY: 374 AN XY: 73960

African (AFR) AF: 0.00213 AC: 88 AN: 41278

American (AMR) AF: 0.00619 AC: 94 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00924 AC: 32 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4760

European-Finnish (FIN) AF: 0.00238 AC: 25 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00813 AC: 551 AN: 67812

Other (OTH) AF: 0.00667 AC: 14 AN: 2100

Alfa AF: 0.000922 Hom.: 0

Bravo AF: 0.00569

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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: rs200455639; hg19: chr3-49547839;