rs61104194

chr2-71515606-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.760-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 1,613,696 control chromosomes in the GnomAD database, including 7,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1303 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5756 hom.)
• Consequence: DYSF NM_001130987.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.899

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=-0.87).
• BP6: Variant 2-71515606-C-T is Benign according to our data. Variant chr2-71515606-C-T is described in ClinVar as [Benign]. Clinvar id is 94356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71515606-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.760-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.664-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.664-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.760-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17213 AN: 151988 Hom.: 1300 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0854

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.00463

Gnomad SAS AF: 0.0442

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0897

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0766 AC: 19231 AN: 251094 Hom.: 1071 AF XY: 0.0755 AC XY: 10248 AN XY: 135764

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0589

Gnomad EAS exome AF: 0.00217

Gnomad SAS exome AF: 0.0463

Gnomad FIN exome AF: 0.0461

Gnomad NFE exome AF: 0.0919

Gnomad OTH exome AF: 0.0825

GnomAD4 exome AF: 0.0826 AC: 120774 AN: 1461590 Hom.: 5756 Cov.: 31 AF XY: 0.0814 AC XY: 59196 AN XY: 727092

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.0574

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0477

Gnomad4 FIN exome AF: 0.0460

Gnomad4 NFE exome AF: 0.0874

Gnomad4 OTH exome AF: 0.0841

GnomAD4 genome AF: 0.113 AC: 17233 AN: 152106 Hom.: 1303 Cov.: 32 AF XY: 0.108 AC XY: 8059 AN XY: 74374

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0852

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.0438

Gnomad4 FIN AF: 0.0421

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0903 Hom.: 136

Bravo AF: 0.121

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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. -
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	-	- -

Distal myopathy with anterior tibial onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Miyoshi muscular dystrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Qualitative or quantitative defects of dysferlin Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.40
Dann	Benign	0.37

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: rs61104194; hg19: chr2-71742736; COSMIC: COSV50315338;