rs4852800

Variant names:

• chr2-71528250-A-G
• rs4852800
• NM_001130987.2:c.1277-48A>G

Variant summary

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

The NM_001130987.2(DYSF):​c.1277-48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,536,098 control chromosomes in the GnomAD database, including 497,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50265 hom., cov: 32)
  • Exomes 𝑓: 0.80 (447632 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0510
• Publications: 8 publications found

Genes affected

DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

DYSF Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-71528250-A-G is Benign according to our data. Variant chr2-71528250-A-G is described in ClinVar as Benign. ClinVar VariationId is 259065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. 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
	DYSF	NM_001130987.2	MANE Select	c.1277-48A>G		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.1181-48A>G		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.1274-48A>G		intron	N/A	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.1277-48A>G		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1181-48A>G		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.1274-48A>G		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121834 AN: 152072 Hom.: 50212 Cov.: 32

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.806

GnomAD2 exomes AF: 0.733 AC: 166725 AN: 227464 AF XY: 0.731

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.685

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.832

Gnomad OTH exome AF: 0.774

GnomAD4 exome AF: 0.795 AC: 1100315 AN: 1383908 Hom.: 447632 Cov.: 20 AF XY: 0.790 AC XY: 545399 AN XY: 690732

African (AFR) AF: 0.892 AC: 28615 AN: 32080

American (AMR) AF: 0.697 AC: 28527 AN: 40954

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 21796 AN: 25374

East Asian (EAS) AF: 0.218 AC: 8515 AN: 38990

South Asian (SAS) AF: 0.594 AC: 48835 AN: 82258

European-Finnish (FIN) AF: 0.785 AC: 41271 AN: 52544

Middle Eastern (MID) AF: 0.818 AC: 4608 AN: 5634

European-Non Finnish (NFE) AF: 0.833 AC: 873132 AN: 1048284

Other (OTH) AF: 0.779 AC: 45016 AN: 57790

GnomAD4 genome AF: 0.801 AC: 121948 AN: 152190 Hom.: 50265 Cov.: 32 AF XY: 0.788 AC XY: 58659 AN XY: 74424

African (AFR) AF: 0.887 AC: 36839 AN: 41530

American (AMR) AF: 0.732 AC: 11197 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2983 AN: 3472

East Asian (EAS) AF: 0.201 AC: 1040 AN: 5178

South Asian (SAS) AF: 0.551 AC: 2655 AN: 4818

European-Finnish (FIN) AF: 0.777 AC: 8235 AN: 10604

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56307 AN: 67980

Other (OTH) AF: 0.802 AC: 1696 AN: 2114

Alfa AF: 0.824 Hom.: 10926

Bravo AF: 0.803

Asia WGS AF: 0.429 AC: 1496 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Distal myopathy with anterior tibial onset (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.3
DANN	Benign	0.59
PhyloP100		0.051
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4852800; hg19: chr2-71755380; COSMIC: COSV50340320;