chr2-71598754-G-T

Variant names:

• chr2-71598754-G-T
• rs191746041
• NM_001130987.2:c.3756+9G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS1

The NM_001130987.2(DYSF):​c.3756+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,610,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 0.717

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000808 (123/152314) while in subpopulation AMR AF= 0.00235 (36/15300). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3756+9G>T		intron_variant	Intron 33 of 55	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3702+9G>T		intron_variant	Intron 33 of 54	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3756+9G>T		intron_variant	Intron 33 of 55	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.3702+9G>T		intron_variant	Intron 33 of 54	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000590 AC: 145 AN: 245920 Hom.: 0 AF XY: 0.000600 AC XY: 80 AN XY: 133440

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000582

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000475 AC: 692 AN: 1458164 Hom.: 0 Cov.: 32 AF XY: 0.000489 AC XY: 355 AN XY: 725458

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000900 AC XY: 67 AN XY: 74478

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000670 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 26, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 05, 2014	Variant classified as Uncertain Significance - Favor Benign. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2018	This variant is associated with the following publications: (PMID: 23519732, 27884173) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Qualitative or quantitative defects of dysferlin Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 15, 2018	The DYSF c.3702+9G>T variant has been reported in one study and in one patient in a compound heterozygous state with a missense variant (Nilsson et al. 2013). Control data are not available for this variant, which is reported at a frequency of 0.01327 in the Mandinka in Gambia population of the 1000 Genomes Project. Functional studies using immunohistochemical staining of quadriceps muscle from the patient showed an absence of membrane-bound dysferlin secondary to the intracellular aggregation of the variant protein. Quantitative RT-PCR and Western blotting showed that intracellular total mRNA and protein levels were increased two- to three-fold respectively compared to healthy controls. Human splicing finder predicts the variant to be deleterious and to destroy a donor splice site in intron 33 likely causing an excision of the coding region required for domain C2D of the protein (exon 33) (Nilsson et al. 2013). Based on the evidence, the c.3702+9G>T variant is classified as a variant of unknown significance but suspicioud for pathogenicity for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2025	- -

DYSF-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2024

The DYSF c.3702+9G>T variant is predicted to interfere with splicing. This variant has been reported in the heterozygous state in an individual with Miyoshi myopathy (Table 2, Nilsson et al. 2013. PubMed ID: 23519732). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.71

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: rs191746041; hg19: chr2-71825884;