rs62145939

Positions:

• chr2-71658970-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_001130987.2(DYSF):​c.4848G>A​(p.Glu1616=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,614,160 control chromosomes in the GnomAD database, including 487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (27 hom., cov: 32)
  • Exomes 𝑓: 0.023 (460 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 1.68

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=1.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2465/152276) while in subpopulation NFE AF= 0.0246 (1673/68008). AF 95% confidence interval is 0.0236. There are 27 homozygotes in gnomad4. There are 1232 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4848G>A	p.Glu1616=	synonymous_variant	44/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4731G>A	p.Glu1577=	synonymous_variant	43/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4848G>A	p.Glu1616=	synonymous_variant	44/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.4731G>A	p.Glu1577=	synonymous_variant	43/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2467 AN: 152158 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0181 AC: 4548 AN: 251472 Hom.: 55 AF XY: 0.0188 AC XY: 2553 AN XY: 135902

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00908

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0234 AC: 34184 AN: 1461884 Hom.: 460 Cov.: 31 AF XY: 0.0232 AC XY: 16879 AN XY: 727240

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.0393

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.0162 AC: 2465 AN: 152276 Hom.: 27 Cov.: 32 AF XY: 0.0165 AC XY: 1232 AN XY: 74460

Gnomad4 AFR AF: 0.00508

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0230 Hom.: 14

Bravo AF: 0.0160

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0279

EpiControl AF: 0.0287

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Qualitative or quantitative defects of dysferlin Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.3
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62145939; hg19: chr2-71886100;