chr3-49510575-C-G

Variant names:

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

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.41C>G​(p.Ser14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,856 control chromosomes in the GnomAD database, including 800,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.98 (72546 hom., cov: 27)
  • Exomes 𝑓: 1.0 (727481 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2135001E-6).
• BP6: Variant 3-49510575-C-G is Benign according to our data. Variant chr3-49510575-C-G is described in ClinVar as Benign. ClinVar VariationId is 226558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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.41C>G	p.Ser14Trp	missense	Exon 2 of 3	NP_004384.5
	DAG1	NM_001165928.4		c.41C>G	p.Ser14Trp	missense	Exon 5 of 6	NP_001159400.3
	DAG1	NM_001177634.3		c.41C>G	p.Ser14Trp	missense	Exon 5 of 6	NP_001171105.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000308775.7	TSL:1 MANE Select	c.41C>G	p.Ser14Trp	missense	Exon 2 of 3	ENSP00000312435.2
	DAG1	ENST00000479935.1	TSL:1	n.352C>G		non_coding_transcript_exon	Exon 1 of 2
	DAG1	ENST00000418588.6	TSL:3	c.41C>G	p.Ser14Trp	missense	Exon 3 of 4	ENSP00000405859.2

Frequencies

GnomAD3 genomes AF: 0.976 AC: 148289 AN: 151908 Hom.: 72491 Cov.: 27

Gnomad AFR AF: 0.916

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.999

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.987

GnomAD2 exomes AF: 0.994 AC: 249425 AN: 251000 AF XY: 0.995

Gnomad AFR exome AF: 0.914

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.998 AC: 1458269 AN: 1461830 Hom.: 727481 Cov.: 78 AF XY: 0.998 AC XY: 725686 AN XY: 727212

African (AFR) AF: 0.914 AC: 30612 AN: 33480

American (AMR) AF: 0.996 AC: 44524 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86232 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53369 AN: 53370

Middle Eastern (MID) AF: 0.998 AC: 5747 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1111864 AN: 1112010

Other (OTH) AF: 0.995 AC: 60085 AN: 60396

GnomAD4 genome AF: 0.976 AC: 148403 AN: 152026 Hom.: 72546 Cov.: 27 AF XY: 0.976 AC XY: 72563 AN XY: 74322

African (AFR) AF: 0.917 AC: 37956 AN: 41412

American (AMR) AF: 0.992 AC: 15132 AN: 15248

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4798 AN: 4800

European-Finnish (FIN) AF: 1.00 AC: 10606 AN: 10606

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67983 AN: 68002

Other (OTH) AF: 0.987 AC: 2081 AN: 2108

Alfa AF: 0.943 Hom.: 16724

Bravo AF: 0.973

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.921 AC: 4059

ESP6500EA AF: 1.00 AC: 8596

ExAC AF: 0.992 AC: 120479

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2P (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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Benign	0.16
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.090	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.37
ClinPred		0.0070	T
GERP RS		4.7
Varity_R		0.027
gMVP		0.42
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: rs2131107; hg19: chr3-49548008; COSMIC: COSV107353611; COSMIC: COSV107353611;