rs74384941

Variant names:

• chr2-71516281-T-C
• rs74384941
• NM_001130987.2:c.951+39T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130987.2(DYSF):​c.951+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,592,796 control chromosomes in the GnomAD database, including 1,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (129 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1228 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.102
• Publications: 1 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 2-71516281-T-C is Benign according to our data. Variant chr2-71516281-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0323 (4922/152348) while in subpopulation NFE AF = 0.0404 (2746/68040). AF 95% confidence interval is 0.0391. There are 129 homozygotes in GnomAd4. There are 2621 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 129 AR gene

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.951+39T>C		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.855+39T>C		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.948+39T>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.951+39T>C		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.855+39T>C		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.948+39T>C		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4922 AN: 152230 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.00825

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0945

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0357 AC: 8918 AN: 249852 AF XY: 0.0358

Gnomad AFR exome AF: 0.00675

Gnomad AMR exome AF: 0.0353

Gnomad ASJ exome AF: 0.00854

Gnomad EAS exome AF: 0.00956

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.0425

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0385 AC: 55424 AN: 1440448 Hom.: 1228 Cov.: 28 AF XY: 0.0377 AC XY: 27033 AN XY: 717956

African (AFR) AF: 0.00630 AC: 208 AN: 33008

American (AMR) AF: 0.0345 AC: 1542 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 235 AN: 26008

East Asian (EAS) AF: 0.00538 AC: 213 AN: 39572

South Asian (SAS) AF: 0.0133 AC: 1138 AN: 85810

European-Finnish (FIN) AF: 0.0881 AC: 4701 AN: 53352

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5736

European-Non Finnish (NFE) AF: 0.0415 AC: 45330 AN: 1092624

Other (OTH) AF: 0.0330 AC: 1973 AN: 59702

GnomAD4 genome AF: 0.0323 AC: 4922 AN: 152348 Hom.: 129 Cov.: 33 AF XY: 0.0352 AC XY: 2621 AN XY: 74488

African (AFR) AF: 0.00823 AC: 342 AN: 41580

American (AMR) AF: 0.0383 AC: 586 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5186

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4826

European-Finnish (FIN) AF: 0.0945 AC: 1003 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0404 AC: 2746 AN: 68040

Other (OTH) AF: 0.0388 AC: 82 AN: 2116

Alfa AF: 0.0334 Hom.: 19

Bravo AF: 0.0285

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.51
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74384941; hg19: chr2-71743411;