2-71526357-C-T

Position:

chr2-71526357-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_001130987.2(DYSF):c.1276+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,473,386 control chromosomes in the GnomAD database, including 14,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1714 hom., cov: 31)

Exomes 𝑓: 0.14 ( 13274 hom. )

Consequence

DYSF
NM_001130987.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.83

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 2-71526357-C-T is Benign according to our data. Variant chr2-71526357-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71526357-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.1276+11C>T		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4 linkuse as main transcript	c.1180+11C>T		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8 linkuse as main transcript	c.1180+11C>T		intron_variant		1	NM_003494.4	ENSP00000258104	A1	O75923-1
DYSF	ENST00000410020.8 linkuse as main transcript	c.1276+11C>T		intron_variant		1	NM_001130987.2	ENSP00000386881	A1	O75923-13

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

21695

AN:

145092

Hom.:

1712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.0889

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.119

Gnomad NFE

AF:

0.144

Gnomad OTH

AF:

0.148

GnomAD3 exomes

AF:

0.116

AC:

28744

AN:

247926

Hom.:

2065

AF XY:

0.117

AC XY:

15717

AN XY:

134438

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.0737

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.00349

Gnomad SAS exome

AF:

0.0869

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.142

AC:

189023

AN:

1328178

Hom.:

13274

Cov.:

AF XY:

0.141

AC XY:

93290

AN XY:

659506

show subpopulations

Gnomad4 AFR exome

AF:

0.218

Gnomad4 AMR exome

AF:

0.0878

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.00424

Gnomad4 SAS exome

AF:

0.0920

Gnomad4 FIN exome

AF:

0.149

Gnomad4 NFE exome

AF:

0.149

Gnomad4 OTH exome

AF:

0.147

GnomAD4 genome

AF:

0.149

AC:

21705

AN:

145208

Hom.:

1714

Cov.:

AF XY:

0.147

AC XY:

10364

AN XY:

70704

show subpopulations

Gnomad4 AFR

AF:

0.199

Gnomad4 AMR

AF:

0.122

Gnomad4 ASJ

AF:

0.104

Gnomad4 EAS

AF:

0.00660

Gnomad4 SAS

AF:

0.0878

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.144

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.131

Hom.:

286

Bravo

AF:

0.145

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.1276+11C>T in intron 13 of DYSF: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 18.7% (824/4406) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs35982795). -

Qualitative or quantitative defects of dysferlin

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely 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

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Jul 30, 2021

- -

Miyoshi myopathy

Benign:1

Likely 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

-0.91

CADD

Benign

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.93

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over