rs11903960

Variant names:

• chr2-71516246-T-C
• rs11903960
• NM_001130987.2:c.951+4T>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.951+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 1,613,410 control chromosomes in the GnomAD database, including 6,944 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (748 hom., cov: 33)
  • Exomes 𝑓: 0.089 (6196 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002590
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.52
• Publications: 7 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=-0.8).
• BP6: Variant 2-71516246-T-C is Benign according to our data. Variant chr2-71516246-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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.951+4T>C		splice_region intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.855+4T>C		splice_region intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.948+4T>C		splice_region intron	N/A	NP_001124453.1	O75923-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.951+4T>C		splice_region intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.855+4T>C		splice_region intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.948+4T>C		splice_region intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0965 AC: 14678 AN: 152158 Hom.: 746 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0820

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0886

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0792 AC: 19913 AN: 251300 AF XY: 0.0782

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0594

Gnomad ASJ exome AF: 0.0948

Gnomad EAS exome AF: 0.0299

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0884

Gnomad OTH exome AF: 0.0794

GnomAD4 exome AF: 0.0889 AC: 129862 AN: 1461134 Hom.: 6196 Cov.: 32 AF XY: 0.0872 AC XY: 63350 AN XY: 726900

African (AFR) AF: 0.124 AC: 4160 AN: 33458

American (AMR) AF: 0.0610 AC: 2727 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 2558 AN: 26132

East Asian (EAS) AF: 0.0247 AC: 981 AN: 39696

South Asian (SAS) AF: 0.0499 AC: 4304 AN: 86242

European-Finnish (FIN) AF: 0.107 AC: 5692 AN: 53412

Middle Eastern (MID) AF: 0.0678 AC: 391 AN: 5764

European-Non Finnish (NFE) AF: 0.0932 AC: 103546 AN: 1111354

Other (OTH) AF: 0.0912 AC: 5503 AN: 60368

GnomAD4 genome AF: 0.0965 AC: 14697 AN: 152276 Hom.: 748 Cov.: 33 AF XY: 0.0968 AC XY: 7209 AN XY: 74470

African (AFR) AF: 0.126 AC: 5220 AN: 41540

American (AMR) AF: 0.0822 AC: 1258 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 333 AN: 3470

East Asian (EAS) AF: 0.0292 AC: 151 AN: 5174

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4828

European-Finnish (FIN) AF: 0.109 AC: 1159 AN: 10618

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0886 AC: 6026 AN: 68020

Other (OTH) AF: 0.104 AC: 219 AN: 2114

Alfa AF: 0.0929 Hom.: 1156

Bravo AF: 0.0972

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0891

EpiControl AF: 0.0866

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (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	-0.80
CADD	Benign	0.0010
DANN	Benign	0.62
PhyloP100		-3.5
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0080
Splicevardb		2.0
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: rs11903960; hg19: chr2-71743376;