rs61104194

Variant names:

• chr2-71515606-C-T
• rs61104194
• NM_001130987.2:c.760-17C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.760-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 1,613,696 control chromosomes in the GnomAD database, including 7,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1303 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5756 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.899
• 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-71515606-C-T is Benign according to our data. Variant chr2-71515606-C-T is described in ClinVar as Benign. ClinVar VariationId is 94356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

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.760-17C>T		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.664-17C>T		intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.757-17C>T		intron	N/A	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.760-17C>T		intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.664-17C>T		intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.757-17C>T		intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17213 AN: 151988 Hom.: 1300 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0854

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.00463

Gnomad SAS AF: 0.0442

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0897

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0766 AC: 19231 AN: 251094 AF XY: 0.0755

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0589

Gnomad EAS exome AF: 0.00217

Gnomad FIN exome AF: 0.0461

Gnomad NFE exome AF: 0.0919

Gnomad OTH exome AF: 0.0825

GnomAD4 exome AF: 0.0826 AC: 120774 AN: 1461590 Hom.: 5756 Cov.: 31 AF XY: 0.0814 AC XY: 59196 AN XY: 727092

African (AFR) AF: 0.216 AC: 7226 AN: 33468

American (AMR) AF: 0.0574 AC: 2566 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 1536 AN: 26130

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39696

South Asian (SAS) AF: 0.0477 AC: 4112 AN: 86250

European-Finnish (FIN) AF: 0.0460 AC: 2456 AN: 53394

Middle Eastern (MID) AF: 0.0942 AC: 543 AN: 5762

European-Non Finnish (NFE) AF: 0.0874 AC: 97178 AN: 1111800

Other (OTH) AF: 0.0841 AC: 5080 AN: 60374

GnomAD4 genome AF: 0.113 AC: 17233 AN: 152106 Hom.: 1303 Cov.: 32 AF XY: 0.108 AC XY: 8059 AN XY: 74374

African (AFR) AF: 0.209 AC: 8644 AN: 41440

American (AMR) AF: 0.0852 AC: 1303 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 181 AN: 3472

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5174

South Asian (SAS) AF: 0.0438 AC: 211 AN: 4812

European-Finnish (FIN) AF: 0.0421 AC: 446 AN: 10606

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0896 AC: 6095 AN: 67988

Other (OTH) AF: 0.106 AC: 223 AN: 2110

Alfa AF: 0.0903 Hom.: 136

Bravo AF: 0.121

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Distal myopathy with anterior tibial onset (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	-	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.37
PhyloP100		-0.90
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: rs61104194; hg19: chr2-71742736; COSMIC: COSV50315338;