2-71598745-T-C

Variant names:

• chr2-71598745-T-C
• rs141720146
• NM_001130987.2:c.3756T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001130987.2(DYSF):​c.3756T>C​(p.Tyr1252Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,611,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005868
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.45
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-71598745-T-C is Benign according to our data. Variant chr2-71598745-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167024.

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.3756T>C	p.Tyr1252Tyr	splice_region synonymous	Exon 33 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.3702T>C	p.Tyr1234Tyr	splice_region synonymous	Exon 33 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.3753T>C	p.Tyr1251Tyr	splice_region synonymous	Exon 33 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.3756T>C	p.Tyr1252Tyr	splice_region synonymous	Exon 33 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3702T>C	p.Tyr1234Tyr	splice_region synonymous	Exon 33 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.3753T>C	p.Tyr1251Tyr	splice_region synonymous	Exon 33 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000165 AC: 41 AN: 247844 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1459472 Hom.: 1 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 726048

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000176 AC: 196 AN: 1111980

Other (OTH) AF: 0.000199 AC: 12 AN: 60376

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000785 AC: 12 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000196

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.010
DANN	Benign	0.63
PhyloP100		-3.4
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.10
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: rs141720146; hg19: chr2-71825875;