NM_001130987.2:c.240-8248A>G

Variant names:

• chr2-71494966-A-G
• rs4852261
• NM_001130987.2:c.240-8248A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130987.2(DYSF):​c.240-8248A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 152,236 control chromosomes in the GnomAD database, including 58,107 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (58107 hom., cov: 33)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.240-8248A>G		intron_variant	Intron 3 of 55	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.237-8248A>G		intron_variant	Intron 3 of 54	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.240-8248A>G		intron_variant	Intron 3 of 55	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.237-8248A>G		intron_variant	Intron 3 of 54	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132692 AN: 152118 Hom.: 58068 Cov.: 33

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.872

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.872 AC: 132789 AN: 152236 Hom.: 58107 Cov.: 33 AF XY: 0.877 AC XY: 65266 AN XY: 74448

African (AFR) AF: 0.820 AC: 34011 AN: 41500

American (AMR) AF: 0.903 AC: 13815 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3329 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5175 AN: 5184

South Asian (SAS) AF: 0.953 AC: 4593 AN: 4820

European-Finnish (FIN) AF: 0.885 AC: 9395 AN: 10612

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59548 AN: 68032

Other (OTH) AF: 0.873 AC: 1846 AN: 2114

Alfa AF: 0.879 Hom.: 114350

Bravo AF: 0.871

Asia WGS AF: 0.964 AC: 3354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.47
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: rs4852261; hg19: chr2-71722096;