2-71453820-C-A

Position:

• chr2-71453820-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003494.4(DYSF):​c.-179C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 674,250 control chromosomes in the GnomAD database, including 7,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1970 hom., cov: 32)
  • Exomes 𝑓: 0.12 (5686 hom.)
• Consequence: DYSF NM_003494.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.122

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]

ENSG00000289327 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-71453820-C-A is Benign according to our data. Variant chr2-71453820-C-A is described in ClinVar as [Benign]. Clinvar id is 681717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_003494.4	c.-179C>A		5_prime_UTR_variant	1/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104	c.-179C>A		5_prime_UTR_variant	1/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20410 AN: 152030 Hom.: 1970 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.116 AC: 60766 AN: 522102 Hom.: 5686 Cov.: 6 AF XY: 0.116 AC XY: 32288 AN XY: 277950

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.0764

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.134 AC: 20430 AN: 152148 Hom.: 1970 Cov.: 32 AF XY: 0.139 AC XY: 10350 AN XY: 74372

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0744

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0947 Hom.: 341

Bravo AF: 0.141

Asia WGS AF: 0.299 AC: 1037 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Qualitative or quantitative defects of dysferlin Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.8
DANN	Benign	0.92

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: rs6741336; hg19: chr2-71680950; COSMIC: COSV50528780;