2-71453820-C-A

Variant names:

• chr2-71453820-C-A
• rs6741336
• NM_003494.4:c.-179C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289327 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
DYSF	NM_003494.4	c.-179C>A		5_prime_UTR_variant	Exon 1 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.-179C>A		5_prime_UTR_variant	Exon 1 of 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

African (AFR) AF: 0.216 AC: 3218 AN: 14880

American (AMR) AF: 0.105 AC: 3237 AN: 30852

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 2258 AN: 17096

East Asian (EAS) AF: 0.430 AC: 13453 AN: 31308

South Asian (SAS) AF: 0.139 AC: 7800 AN: 56044

European-Finnish (FIN) AF: 0.105 AC: 3443 AN: 32686

Middle Eastern (MID) AF: 0.132 AC: 312 AN: 2356

European-Non Finnish (NFE) AF: 0.0764 AC: 23560 AN: 308188

Other (OTH) AF: 0.121 AC: 3485 AN: 28692

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

African (AFR) AF: 0.209 AC: 8687 AN: 41492

American (AMR) AF: 0.105 AC: 1605 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 438 AN: 3472

East Asian (EAS) AF: 0.466 AC: 2394 AN: 5138

South Asian (SAS) AF: 0.153 AC: 741 AN: 4828

European-Finnish (FIN) AF: 0.108 AC: 1148 AN: 10612

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0744 AC: 5058 AN: 67978

Other (OTH) AF: 0.123 AC: 259 AN: 2114

Alfa AF: 0.0956 Hom.: 416

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.12
PromoterAI		-0.057	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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