rs13424178

Positions:

• chr2-71553776-C-A
• chr2-71553776-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.1985-31C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 674,188 control chromosomes in the GnomAD database, including 2,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (144 hom., cov: 29)
  • Exomes 𝑓: 0.13 (2068 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.964

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=-0.81).
• BP6: Variant 2-71553776-C-A is Benign according to our data. Variant chr2-71553776-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 259067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71553776-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1985-31C>A		intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.1931-31C>A		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.1931-31C>A		intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.1985-31C>A		intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 5531 AN: 134268 Hom.: 144 Cov.: 29

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.0654

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000276

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0563

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0363 AC: 8002 AN: 220410 Hom.: 187 AF XY: 0.0376 AC XY: 4446 AN XY: 118360

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.000181

Gnomad SAS exome AF: 0.0359

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.129 AC: 69530 AN: 539826 Hom.: 2068 Cov.: 18 AF XY: 0.119 AC XY: 34147 AN XY: 287344

Gnomad4 AFR exome AF: 0.0403

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.0000771

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.0322

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.0412 AC: 5534 AN: 134362 Hom.: 144 Cov.: 29 AF XY: 0.0393 AC XY: 2525 AN XY: 64246

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.0398

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.000276

Gnomad4 SAS AF: 0.0443

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0318 Hom.: 23

Bravo AF: 0.0367

Asia WGS AF: 0.0120 AC: 43 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.7
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs13424178; hg19: chr2-71780906;