NM_001130987.2:c.4062C>A

Variant names:

• chr2-71611467-C-A
• rs2303606
• NM_001130987.2:c.4062C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 94316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4062C>A	p.Ile1354Ile	splice_region_variant, synonymous_variant	Exon 38 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4008C>A	p.Ile1336Ile	splice_region_variant, synonymous_variant	Exon 38 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4062C>A	p.Ile1354Ile	splice_region_variant, synonymous_variant	Exon 38 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4008C>A	p.Ile1336Ile	splice_region_variant, synonymous_variant	Exon 38 of 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

GnomAD2 exomes AF: 0.504 AC: 126574 AN: 251100 AF XY: 0.501

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 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

African (AFR) AF: 0.394 AC: 13186 AN: 33478

American (AMR) AF: 0.540 AC: 24170 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 15595 AN: 26136

East Asian (EAS) AF: 0.469 AC: 18627 AN: 39700

South Asian (SAS) AF: 0.429 AC: 37040 AN: 86256

European-Finnish (FIN) AF: 0.538 AC: 28707 AN: 53354

Middle Eastern (MID) AF: 0.486 AC: 2805 AN: 5768

European-Non Finnish (NFE) AF: 0.508 AC: 565412 AN: 1111928

Other (OTH) AF: 0.500 AC: 30171 AN: 60392

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

African (AFR) AF: 0.398 AC: 16496 AN: 41472

American (AMR) AF: 0.503 AC: 7699 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2116 AN: 3472

East Asian (EAS) AF: 0.473 AC: 2440 AN: 5162

South Asian (SAS) AF: 0.432 AC: 2082 AN: 4822

European-Finnish (FIN) AF: 0.528 AC: 5589 AN: 10588

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34633 AN: 67956

Other (OTH) AF: 0.502 AC: 1060 AN: 2110

Alfa AF: 0.509 Hom.: 36483

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

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Distal myopathy with anterior tibial onset Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi myopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.8
DANN	Benign	0.50
PhyloP100		0.35
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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