chr2-71682692-C-T

Position:

• chr2-71682692-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.6321+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,611,110 control chromosomes in the GnomAD database, including 38,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3171 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35555 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.07

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=-0.89).
• BP6: Variant 2-71682692-C-T is Benign according to our data. Variant chr2-71682692-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71682692-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.6321+15C>T		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.6204+15C>T		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.6321+15C>T		intron_variant		1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.6204+15C>T		intron_variant		1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29562 AN: 151902 Hom.: 3165 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0844

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.204

GnomAD3 exomes AF: 0.201 AC: 48904 AN: 243902 Hom.: 5384 AF XY: 0.208 AC XY: 27495 AN XY: 131898

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0855

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.217 AC: 316114 AN: 1459090 Hom.: 35555 Cov.: 35 AF XY: 0.218 AC XY: 158119 AN XY: 725622

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.0945

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.195 AC: 29588 AN: 152020 Hom.: 3171 Cov.: 32 AF XY: 0.196 AC XY: 14568 AN XY: 74306

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0842

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.205

Alfa AF: 0.213 Hom.: 2698

Bravo AF: 0.178

Asia WGS AF: 0.189 AC: 654 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.6321+15C>T in intron 55 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 22.9% (1966/8598) of European American chromos omes from a broad population by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS; dbSNP rs2559082). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

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

Jun 10, 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	-0.89
CADD	Benign	0.61
DANN	Benign	0.45

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: rs2559082; hg19: chr2-71909822; COSMIC: COSV50340743;