2-71598547-C-T

Position:

• chr2-71598547-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.3575-17C>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 0.038 in 1,614,046 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (227 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1207 hom.)
• Consequence: DYSF NM_001130987.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.11

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=-0.95).
• BP6: Variant 2-71598547-C-T is Benign according to our data. Variant chr2-71598547-C-T is described in ClinVar as [Benign]. Clinvar id is 94306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71598547-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3575-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3521-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.3521-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.3575-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7253 AN: 152212 Hom.: 227 Cov.: 33

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0339 AC: 8479 AN: 250062 Hom.: 206 AF XY: 0.0332 AC XY: 4498 AN XY: 135306

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0342

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0370 AC: 54091 AN: 1461716 Hom.: 1207 Cov.: 32 AF XY: 0.0369 AC XY: 26845 AN XY: 727166

Gnomad4 AFR exome AF: 0.0864

Gnomad4 AMR exome AF: 0.0253

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0405

GnomAD4 genome AF: 0.0477 AC: 7263 AN: 152330 Hom.: 227 Cov.: 33 AF XY: 0.0451 AC XY: 3357 AN XY: 74490

Gnomad4 AFR AF: 0.0836

Gnomad4 AMR AF: 0.0352

Gnomad4 ASJ AF: 0.0472

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0344

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0388

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0208 Hom.: 13

Asia WGS AF: 0.0190 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

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

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.066
DANN	Benign	0.63

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: rs13421969; hg19: chr2-71825677;