2-71611467-C-A

Position:

• chr2-71611467-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):​c.4062C>A​(p.Ile1354Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,613,814 control chromosomes in the GnomAD database, including 203,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17599 hom., cov: 33)
  • Exomes 𝑓: 0.50 (186255 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.354

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]

DYSF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-71611467-C-A is Benign according to our data. Variant chr2-71611467-C-A is described in ClinVar as [Benign]. Clinvar id is 94316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71611467-C-A is described in Lovd as [Benign]. Variant chr2-71611467-C-A is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=0.354 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4062C>A	p.Ile1354Ile	splice_region_variant, synonymous_variant	38/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4008C>A	p.Ile1336Ile	splice_region_variant, synonymous_variant	38/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4062C>A	p.Ile1354Ile	splice_region_variant, synonymous_variant	38/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4008C>A	p.Ile1336Ile	splice_region_variant, synonymous_variant	38/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72686 AN: 151964 Hom.: 17597 Cov.: 33

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.501

GnomAD3 exomes AF: 0.504 AC: 126574 AN: 251100 Hom.: 32368 AF XY: 0.501 AC XY: 68102 AN XY: 135814

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.468

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.503 AC: 735713 AN: 1461732 Hom.: 186255 Cov.: 70 AF XY: 0.502 AC XY: 365248 AN XY: 727170

Gnomad4 AFR exome AF: 0.394

Gnomad4 AMR exome AF: 0.540

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.469

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.478 AC: 72721 AN: 152082 Hom.: 17599 Cov.: 33 AF XY: 0.477 AC XY: 35490 AN XY: 74342

Gnomad4 AFR AF: 0.398

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.510

Gnomad4 OTH AF: 0.502

Alfa AF: 0.513 Hom.: 29939

Bravo AF: 0.479

Asia WGS AF: 0.479 AC: 1664 AN: 3478

EpiCase AF: 0.512

EpiControl AF: 0.517

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ile1354Ile in exon 38 of DYSF: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 48.9% (4208/8600) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2303606). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 17, 2017	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Limb-girdle muscular dystrophy, recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Distal myopathy with anterior tibial onset 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

- -

Miyoshi myopathy Benign:1

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	-0.46
CADD	Benign	6.8
DANN	Benign	0.50

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: rs2303606; hg19: chr2-71838597; COSMIC: COSV50280371;