rs2303599

Variant names:

• chr2-71664231-C-T
• rs2303599
• NM_001130987.2:c.5004-37C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-71664231-C-T
• chr2-71664231-C-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.5004-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,612,854 control chromosomes in the GnomAD database, including 582,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.80 (48994 hom., cov: 31)
  • Exomes 𝑓: 0.85 (533871 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.734
• Publications: 6 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

Specifications for DYSF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-71664231-C-T is Benign according to our data. Variant chr2-71664231-C-T is described in ClinVar as Benign. ClinVar VariationId is 259081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.861 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.5004-37C>T		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4887-37C>T		intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.5001-37C>T		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.5004-37C>T		intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4887-37C>T		intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.5001-37C>T		intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121260 AN: 151970 Hom.: 49008 Cov.: 31

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.804

GnomAD2 exomes AF: 0.816 AC: 205013 AN: 251146 AF XY: 0.826

Gnomad AFR exome AF: 0.689

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.868

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.871

Gnomad OTH exome AF: 0.828

GnomAD4 exome AF: 0.853 AC: 1246058 AN: 1460766 Hom.: 533871 Cov.: 46 AF XY: 0.854 AC XY: 620576 AN XY: 726728

African (AFR) AF: 0.685 AC: 22927 AN: 33458

American (AMR) AF: 0.702 AC: 31337 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 22554 AN: 26102

East Asian (EAS) AF: 0.654 AC: 25911 AN: 39638

South Asian (SAS) AF: 0.838 AC: 72096 AN: 86082

European-Finnish (FIN) AF: 0.853 AC: 45469 AN: 53284

Middle Eastern (MID) AF: 0.889 AC: 5121 AN: 5762

European-Non Finnish (NFE) AF: 0.873 AC: 970141 AN: 1111452

Other (OTH) AF: 0.837 AC: 50502 AN: 60318

GnomAD4 genome AF: 0.797 AC: 121280 AN: 152088 Hom.: 48994 Cov.: 31 AF XY: 0.795 AC XY: 59127 AN XY: 74328

African (AFR) AF: 0.691 AC: 28636 AN: 41464

American (AMR) AF: 0.754 AC: 11533 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 2960 AN: 3472

East Asian (EAS) AF: 0.685 AC: 3527 AN: 5148

South Asian (SAS) AF: 0.818 AC: 3947 AN: 4826

European-Finnish (FIN) AF: 0.856 AC: 9068 AN: 10590

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58904 AN: 67984

Other (OTH) AF: 0.796 AC: 1682 AN: 2114

Alfa AF: 0.838 Hom.: 71820

Bravo AF: 0.784

Asia WGS AF: 0.730 AC: 2540 AN: 3478

ClinVar

ClinVar submissions

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	-0.92
CADD	Benign	0.030
DANN	Benign	0.44
PhyloP100		-0.73
Mutation Taster		=20/80	disease causing

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: rs2303599; hg19: chr2-71891361;