3-49510792-G-C

Variant names:

• chr3-49510792-G-C
• rs145403829
• NM_004393.6:c.258G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004393.6(DAG1):​c.258G>C​(p.Leu86Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,614,192 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L86V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.02
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010102391).
• BP6: Variant 3-49510792-G-C is Benign according to our data. Variant chr3-49510792-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195220.
• BS2: High Homozygotes in GnomAd4 at 2 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.258G>C	p.Leu86Phe	missense	Exon 2 of 3	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.258G>C	p.Leu86Phe	missense	Exon 5 of 6	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.258G>C	p.Leu86Phe	missense	Exon 5 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.258G>C	p.Leu86Phe	missense	Exon 2 of 3	ENSP00000312435.2	Q14118
	DAG1	ENST00000479935.1	TSL:1	n.569G>C		non_coding_transcript_exon	Exon 1 of 2
	DAG1	ENST00000418588.6	TSL:3	c.258G>C	p.Leu86Phe	missense	Exon 3 of 4	ENSP00000405859.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152202 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00508

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00289 AC: 725 AN: 251042 AF XY: 0.00290

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00474 AC: 6932 AN: 1461872 Hom.: 22 Cov.: 75 AF XY: 0.00467 AC XY: 3398 AN XY: 727234

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00206 AC: 92 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00168 AC: 145 AN: 86246

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53418

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.00559 AC: 6213 AN: 1112004

Other (OTH) AF: 0.00477 AC: 288 AN: 60396

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152320 Hom.: 2 Cov.: 31 AF XY: 0.00293 AC XY: 218 AN XY: 74474

African (AFR) AF: 0.00103 AC: 43 AN: 41574

American (AMR) AF: 0.00346 AC: 53 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00507 AC: 345 AN: 68036

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00449 Hom.: 8

Bravo AF: 0.00341

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00451

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	2	not specified (3)
-	-	1	DAG1-related disorder (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.0	L
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.23
Sift	Benign	0.24	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.72		Loss of glycosylation at S90 (P = 0.03)
MVP		0.60
MPC		0.30
ClinPred		0.0050	T
GERP RS		4.3
Varity_R		0.038
gMVP		0.51
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: rs145403829; hg19: chr3-49548225; COSMIC: COSV99067795; COSMIC: COSV99067795;