rs76402294

Positions:

• chr2-71549406-C-G
• chr2-71549406-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001130987.2(DYSF):​c.1577-1635C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,610,416 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (88 hom., cov: 31)
  • Exomes 𝑓: 0.021 (379 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.775

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 2-71549406-C-G is Benign according to our data. Variant chr2-71549406-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 94275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71549406-C-G is described in Lovd as [Likely_benign]. Variant chr2-71549406-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0288 (4382/152110) while in subpopulation AFR AF= 0.0477 (1980/41472). AF 95% confidence interval is 0.046. There are 88 homozygotes in gnomad4. There are 2164 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1577-1635C>G		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1522+15C>G		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.1522+15C>G		intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.1577-1635C>G		intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4371 AN: 151992 Hom.: 88 Cov.: 31

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00906

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0212 AC: 5197 AN: 244708 Hom.: 64 AF XY: 0.0202 AC XY: 2666 AN XY: 132248

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.0263

Gnomad ASJ exome AF: 0.00619

Gnomad EAS exome AF: 0.00899

Gnomad SAS exome AF: 0.00427

Gnomad FIN exome AF: 0.0391

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0212 AC: 30942 AN: 1458306 Hom.: 379 Cov.: 31 AF XY: 0.0204 AC XY: 14822 AN XY: 725100

Gnomad4 AFR exome AF: 0.0453

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.00537

Gnomad4 SAS exome AF: 0.00386

Gnomad4 FIN exome AF: 0.0374

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0288 AC: 4382 AN: 152110 Hom.: 88 Cov.: 31 AF XY: 0.0291 AC XY: 2164 AN XY: 74354

Gnomad4 AFR AF: 0.0477

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00908

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0414

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00774 Hom.: 2

Bravo AF: 0.0296

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	4.0
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs76402294; hg19: chr2-71776536;