rs72902605

chr2-71574167-G-Achr2-71574167-G-C

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.3229-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,609,936 control chromosomes in the GnomAD database, including 1,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (586 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (539 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.34

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=-0.92).
• BP6: Variant 2-71574167-G-A is Benign according to our data. Variant chr2-71574167-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71574167-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.3229-31G>A		intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.3175-31G>A		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.3175-31G>A		intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.3229-31G>A		intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7422 AN: 152174 Hom.: 587 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0135 AC: 3340 AN: 246806 Hom.: 257 AF XY: 0.0102 AC XY: 1371 AN XY: 134098

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.00944

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000749

Gnomad OTH exome AF: 0.00890

GnomAD4 exome AF: 0.00547 AC: 7967 AN: 1457644 Hom.: 539 Cov.: 32 AF XY: 0.00473 AC XY: 3430 AN XY: 724598

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0488 AC: 7436 AN: 152292 Hom.: 586 Cov.: 33 AF XY: 0.0468 AC XY: 3483 AN XY: 74476

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0259 Hom.: 44

Bravo AF: 0.0564

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.12
Dann	Benign	0.76

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: rs72902605; hg19: chr2-71801297;