rs74384941

Positions:

• chr2-71516281-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 129 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.951+39T>C		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.855+39T>C		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.951+39T>C		intron_variant		1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.855+39T>C		intron_variant		1	NM_003494.4	ENSP00000258104.3

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

GnomAD3 exomes AF: 0.0357 AC: 8918 AN: 249852 Hom.: 217 AF XY: 0.0358 AC XY: 4832 AN XY: 135102

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 SAS exome AF: 0.0124

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

Gnomad4 AFR exome AF: 0.00630

Gnomad4 AMR exome AF: 0.0345

Gnomad4 ASJ exome AF: 0.00904

Gnomad4 EAS exome AF: 0.00538

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0881

Gnomad4 NFE exome AF: 0.0415

Gnomad4 OTH exome AF: 0.0330

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

Gnomad4 AFR AF: 0.00823

Gnomad4 AMR AF: 0.0383

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00945

Gnomad4 SAS AF: 0.00953

Gnomad4 FIN AF: 0.0945

Gnomad4 NFE AF: 0.0404

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0334 Hom.: 19

Bravo AF: 0.0285

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs74384941; hg19: chr2-71743411;