2-71455820-C-G

Variant names:

• chr2-71455820-C-G
• rs4852259
• NM_003494.4:c.88+1734C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003494.4(DYSF):​c.88+1734C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,966 control chromosomes in the GnomAD database, including 10,663 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10663 hom., cov: 32)
• Consequence: DYSF NM_003494.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0590
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_003494.4	c.88+1734C>G		intron_variant	Intron 1 of 54	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.88+1734C>G		intron_variant	Intron 1 of 54	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55707 AN: 151848 Hom.: 10661 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.382

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.367 AC: 55719 AN: 151966 Hom.: 10663 Cov.: 32 AF XY: 0.366 AC XY: 27215 AN XY: 74268

African (AFR) AF: 0.269 AC: 11147 AN: 41428

American (AMR) AF: 0.500 AC: 7626 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1249 AN: 3468

East Asian (EAS) AF: 0.284 AC: 1463 AN: 5150

South Asian (SAS) AF: 0.471 AC: 2271 AN: 4818

European-Finnish (FIN) AF: 0.320 AC: 3387 AN: 10582

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.403 AC: 27377 AN: 67944

Other (OTH) AF: 0.381 AC: 803 AN: 2108

Alfa AF: 0.372 Hom.: 1382

Bravo AF: 0.374

Asia WGS AF: 0.376 AC: 1308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.75
PhyloP100		0.059
Mutation Taster		=100/0	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: rs4852259; hg19: chr2-71682950;