chr3-49532782-C-T

Variant names:

• chr3-49532782-C-T
• rs78281659
• NM_004393.6:c.2271C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004393.6(DAG1):​c.2271C>T​(p.Ala757Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,062 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: DAG1 NM_004393.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.83
• Publications: 3 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-49532782-C-T is Benign according to our data. Variant chr3-49532782-C-T is described in ClinVar as Benign. ClinVar VariationId is 383114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00741 (1129/152320) while in subpopulation AFR AF = 0.0247 (1025/41566). AF 95% confidence interval is 0.0234. There are 16 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	NM_004393.6	MANE Select	c.2271C>T	p.Ala757Ala	synonymous	Exon 3 of 3	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.2271C>T	p.Ala757Ala	synonymous	Exon 6 of 6	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.2271C>T	p.Ala757Ala	synonymous	Exon 6 of 6	NP_001171105.2	Q14118

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000308775.7	TSL:1 MANE Select	c.2271C>T	p.Ala757Ala	synonymous	Exon 3 of 3	ENSP00000312435.2	Q14118
	DAG1	ENST00000418588.6	TSL:3	c.2271C>T	p.Ala757Ala	synonymous	Exon 4 of 4	ENSP00000405859.2	Q14118
	DAG1	ENST00000421560.6	TSL:4	c.2271C>T	p.Ala757Ala	synonymous	Exon 3 of 3	ENSP00000412067.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1125 AN: 152202 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00229 AC: 574 AN: 250346 AF XY: 0.00184

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00113 AC: 1648 AN: 1461742 Hom.: 18 Cov.: 34 AF XY: 0.00106 AC XY: 772 AN XY: 727170

African (AFR) AF: 0.0279 AC: 934 AN: 33480

American (AMR) AF: 0.00239 AC: 107 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000323 AC: 359 AN: 1112006

Other (OTH) AF: 0.00245 AC: 148 AN: 60388

GnomAD4 genome AF: 0.00741 AC: 1129 AN: 152320 Hom.: 16 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74490

African (AFR) AF: 0.0247 AC: 1025 AN: 41566

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68026

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00356 Hom.: 2

Bravo AF: 0.00804

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.32
DANN	Benign	0.55
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs78281659; hg19: chr3-49570215;