2-71515762-T-C

Variant names:

• chr2-71515762-T-C
• rs13428076
• NM_001130987.2:c.888+11T>C

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.888+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,846 control chromosomes in the GnomAD database, including 14,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1378 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13275 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.467
• Publications: 3 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=-0.89).
• BP6: Variant 2-71515762-T-C is Benign according to our data. Variant chr2-71515762-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.888+11T>C		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.792+11T>C		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.885+11T>C		intron	N/A	NP_001124453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.888+11T>C		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.792+11T>C		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.885+11T>C		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20123 AN: 151996 Hom.: 1374 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0817

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.115 AC: 28795 AN: 251150 AF XY: 0.115

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.0298

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.131 AC: 192192 AN: 1461732 Hom.: 13275 Cov.: 33 AF XY: 0.130 AC XY: 94538 AN XY: 727160

African (AFR) AF: 0.147 AC: 4911 AN: 33480

American (AMR) AF: 0.0786 AC: 3514 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3300 AN: 26134

East Asian (EAS) AF: 0.0248 AC: 983 AN: 39700

South Asian (SAS) AF: 0.0911 AC: 7861 AN: 86254

European-Finnish (FIN) AF: 0.143 AC: 7628 AN: 53360

Middle Eastern (MID) AF: 0.125 AC: 721 AN: 5758

European-Non Finnish (NFE) AF: 0.140 AC: 155370 AN: 1111932

Other (OTH) AF: 0.131 AC: 7904 AN: 60394

GnomAD4 genome AF: 0.133 AC: 20156 AN: 152114 Hom.: 1378 Cov.: 33 AF XY: 0.132 AC XY: 9810 AN XY: 74366

African (AFR) AF: 0.149 AC: 6196 AN: 41496

American (AMR) AF: 0.105 AC: 1612 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3464

East Asian (EAS) AF: 0.0297 AC: 153 AN: 5144

South Asian (SAS) AF: 0.0814 AC: 392 AN: 4816

European-Finnish (FIN) AF: 0.150 AC: 1584 AN: 10580

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9369 AN: 67996

Other (OTH) AF: 0.138 AC: 292 AN: 2114

Alfa AF: 0.125 Hom.: 905

Bravo AF: 0.130

Asia WGS AF: 0.0510 AC: 180 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Distal myopathy with anterior tibial onset (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	-	1	Miyoshi myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.8
DANN	Benign	0.56
PhyloP100		-0.47
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: rs13428076; hg19: chr2-71742892;