rs2303595

Variant names:

• chr2-71552987-C-G
• rs2303595
• NM_001130987.2:c.1807-24C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-71552987-C-G
• chr2-71552987-C-A

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.1807-24C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,613,810 control chromosomes in the GnomAD database, including 2,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1071 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1754 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77
• Publications: 2 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=-0.82).
• BP6: Variant 2-71552987-C-G is Benign according to our data. Variant chr2-71552987-C-G is described in ClinVar as Benign. ClinVar VariationId is 259066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 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.1807-24C>G		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.1753-24C>G		intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1804-24C>G		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.1807-24C>G		intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1753-24C>G		intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1804-24C>G		intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 12692 AN: 152156 Hom.: 1071 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0735

GnomAD2 exomes AF: 0.0434 AC: 10847 AN: 250010 AF XY: 0.0413

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.0285

Gnomad FIN exome AF: 0.00714

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0361 AC: 52715 AN: 1461536 Hom.: 1754 Cov.: 30 AF XY: 0.0364 AC XY: 26480 AN XY: 727040

African (AFR) AF: 0.229 AC: 7676 AN: 33470

American (AMR) AF: 0.0257 AC: 1147 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 569 AN: 26128

East Asian (EAS) AF: 0.0274 AC: 1089 AN: 39692

South Asian (SAS) AF: 0.0582 AC: 5019 AN: 86216

European-Finnish (FIN) AF: 0.00815 AC: 435 AN: 53354

Middle Eastern (MID) AF: 0.0775 AC: 447 AN: 5768

European-Non Finnish (NFE) AF: 0.0302 AC: 33539 AN: 1111828

Other (OTH) AF: 0.0463 AC: 2794 AN: 60382

GnomAD4 genome AF: 0.0835 AC: 12715 AN: 152274 Hom.: 1071 Cov.: 33 AF XY: 0.0805 AC XY: 5993 AN XY: 74460

African (AFR) AF: 0.221 AC: 9180 AN: 41514

American (AMR) AF: 0.0403 AC: 616 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.0307 AC: 159 AN: 5178

South Asian (SAS) AF: 0.0600 AC: 290 AN: 4830

European-Finnish (FIN) AF: 0.00913 AC: 97 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0311 AC: 2117 AN: 68038

Other (OTH) AF: 0.0737 AC: 156 AN: 2116

Alfa AF: 0.0245 Hom.: 24

Bravo AF: 0.0912

Asia WGS AF: 0.0690 AC: 241 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	-0.82
CADD	Benign	13
DANN	Benign	0.59
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2303595; hg19: chr2-71780117; COSMIC: COSV50449313;