rs62145939

Variant names:

• chr2-71658970-G-A
• rs62145939
• NM_001130987.2:c.4848G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001130987.2(DYSF):​c.4848G>A​(p.Glu1616Glu) 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). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• 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:10
• Conservation: PhyloP100: 1.68
• Publications: 5 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

Specifications for DYSF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-71658970-G-A is Benign according to our data. Variant chr2-71658970-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94328.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.4848G>A	p.Glu1616Glu	synonymous	Exon 44 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.4731G>A	p.Glu1577Glu	synonymous	Exon 43 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.4845G>A	p.Glu1615Glu	synonymous	Exon 44 of 56	NP_001124453.1	O75923-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.4848G>A	p.Glu1616Glu	synonymous	Exon 44 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4731G>A	p.Glu1577Glu	synonymous	Exon 43 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.4845G>A	p.Glu1615Glu	synonymous	Exon 44 of 56	ENSP00000386547.3	O75923-7

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

GnomAD2 exomes AF: 0.0181 AC: 4548 AN: 251472 AF XY: 0.0188

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 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

African (AFR) AF: 0.00379 AC: 127 AN: 33480

American (AMR) AF: 0.0122 AC: 545 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0393 AC: 1028 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0101 AC: 867 AN: 86258

European-Finnish (FIN) AF: 0.0155 AC: 829 AN: 53420

Middle Eastern (MID) AF: 0.0251 AC: 145 AN: 5768

European-Non Finnish (NFE) AF: 0.0263 AC: 29264 AN: 1112006

Other (OTH) AF: 0.0228 AC: 1377 AN: 60392

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

African (AFR) AF: 0.00508 AC: 211 AN: 41556

American (AMR) AF: 0.0136 AC: 208 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00706 AC: 34 AN: 4818

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1673 AN: 68008

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.0231 Hom.: 63

Bravo AF: 0.0160

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0279

EpiControl AF: 0.0287

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	1	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Miyoshi myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.3
DANN	Benign	0.53
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62145939; hg19: chr2-71886100;