3-49510128-T-C

Variant names:

• chr3-49510128-T-C
• rs7622302
• NM_004393.6:c.-116-291T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004393.6(DAG1):​c.-116-291T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 407,426 control chromosomes in the GnomAD database, including 18,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6518 hom., cov: 33)
  • Exomes 𝑓: 0.29 (12308 hom.)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.168
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-49510128-T-C is Benign according to our data. Variant chr3-49510128-T-C is described in ClinVar as Benign. ClinVar VariationId is 668114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

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.-116-291T>C		intron	N/A	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-116-291T>C		intron	N/A	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.-116-291T>C		intron	N/A	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.-116-291T>C		intron	N/A	ENSP00000312435.2	Q14118
	DAG1	ENST00000418588.6	TSL:3	c.-116-291T>C		intron	N/A	ENSP00000405859.2	Q14118
	DAG1	ENST00000421560.6	TSL:4	c.-116-291T>C		intron	N/A	ENSP00000412067.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42596 AN: 152040 Hom.: 6516 Cov.: 33

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.288

GnomAD4 exome AF: 0.290 AC: 74050 AN: 255268 Hom.: 12308 AF XY: 0.288 AC XY: 37863 AN XY: 131280

African (AFR) AF: 0.233 AC: 2022 AN: 8670

American (AMR) AF: 0.187 AC: 1766 AN: 9430

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 3927 AN: 8746

East Asian (EAS) AF: 0.0641 AC: 1281 AN: 19986

South Asian (SAS) AF: 0.238 AC: 3212 AN: 13498

European-Finnish (FIN) AF: 0.446 AC: 6788 AN: 15224

Middle Eastern (MID) AF: 0.334 AC: 417 AN: 1250

European-Non Finnish (NFE) AF: 0.307 AC: 49828 AN: 162254

Other (OTH) AF: 0.297 AC: 4809 AN: 16210

GnomAD4 genome AF: 0.280 AC: 42611 AN: 152158 Hom.: 6518 Cov.: 33 AF XY: 0.283 AC XY: 21062 AN XY: 74376

African (AFR) AF: 0.235 AC: 9774 AN: 41518

American (AMR) AF: 0.215 AC: 3287 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1600 AN: 3470

East Asian (EAS) AF: 0.0589 AC: 306 AN: 5194

South Asian (SAS) AF: 0.224 AC: 1080 AN: 4818

European-Finnish (FIN) AF: 0.471 AC: 4984 AN: 10576

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20708 AN: 67988

Other (OTH) AF: 0.286 AC: 603 AN: 2112

Alfa AF: 0.277 Hom.: 924

Bravo AF: 0.258

Asia WGS AF: 0.142 AC: 500 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.62
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs7622302; hg19: chr3-49547561;