rs36122356

Positions:

• chr2-71520793-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):​c.1038C>T​(p.His346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,613,280 control chromosomes in the GnomAD database, including 2,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (395 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2562 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.59

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-71520793-C-T is Benign according to our data. Variant chr2-71520793-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520793-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1038C>T	p.His346=	synonymous_variant	12/56	ENST00000410020.8
DYSF	NM_003494.4	c.942C>T	p.His314=	synonymous_variant	11/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.1038C>T	p.His346=	synonymous_variant	12/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.942C>T	p.His314=	synonymous_variant	11/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9863 AN: 152022 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0961

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0578

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0540

Gnomad OTH AF: 0.0608

GnomAD3 exomes AF: 0.0565 AC: 14197 AN: 251450 Hom.: 515 AF XY: 0.0580 AC XY: 7879 AN XY: 135902

Gnomad AFR exome AF: 0.0972

Gnomad AMR exome AF: 0.0288

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.0504

Gnomad SAS exome AF: 0.0818

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0647

GnomAD4 exome AF: 0.0560 AC: 81883 AN: 1461140 Hom.: 2562 Cov.: 32 AF XY: 0.0569 AC XY: 41336 AN XY: 726890

Gnomad4 AFR exome AF: 0.0992

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.0989

Gnomad4 EAS exome AF: 0.0691

Gnomad4 SAS exome AF: 0.0802

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.0532

Gnomad4 OTH exome AF: 0.0618

GnomAD4 genome AF: 0.0649 AC: 9869 AN: 152140 Hom.: 395 Cov.: 32 AF XY: 0.0637 AC XY: 4739 AN XY: 74390

Gnomad4 AFR AF: 0.0961

Gnomad4 AMR AF: 0.0480

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0575

Gnomad4 SAS AF: 0.0800

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0540

Gnomad4 OTH AF: 0.0616

Alfa AF: 0.0599 Hom.: 225

Bravo AF: 0.0654

Asia WGS AF: 0.0870 AC: 302 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0595

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His346His in exon 12 of DYSF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 9.0% (395/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs36122356). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Qualitative or quantitative defects of dysferlin Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 17, 2017

- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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	-0.69
CADD	Benign	0.32
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs36122356; hg19: chr2-71747923; COSMIC: COSV50334856;