NM_001130987.2:c.3757-12C>T

Variant names:

• chr2-71600690-C-T
• rs114968209
• NM_001130987.2:c.3757-12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130987.2(DYSF):​c.3757-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 1,614,068 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (40 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Scores: Splicing: ADA: 0.00001263
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.21
• Publications: 2 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=-0.89).
• BP6: Variant 2-71600690-C-T is Benign according to our data. Variant chr2-71600690-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00916 (1395/152342) while in subpopulation AFR AF = 0.0168 (699/41592). AF 95% confidence interval is 0.0158. There are 11 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.3757-12C>T		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.3703-12C>T		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.3754-12C>T		intron	N/A	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.3757-12C>T		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3703-12C>T		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.3754-12C>T		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.00916 AC: 1394 AN: 152224 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00598 AC: 1502 AN: 251006 AF XY: 0.00566

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00607

Gnomad NFE exome AF: 0.00680

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00595 AC: 8698 AN: 1461726 Hom.: 40 Cov.: 31 AF XY: 0.00586 AC XY: 4264 AN XY: 727152

African (AFR) AF: 0.0151 AC: 506 AN: 33480

American (AMR) AF: 0.00718 AC: 321 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86258

European-Finnish (FIN) AF: 0.00503 AC: 268 AN: 53258

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.00623 AC: 6929 AN: 1112008

Other (OTH) AF: 0.00667 AC: 403 AN: 60396

GnomAD4 genome AF: 0.00916 AC: 1395 AN: 152342 Hom.: 11 Cov.: 33 AF XY: 0.00890 AC XY: 663 AN XY: 74506

African (AFR) AF: 0.0168 AC: 699 AN: 41592

American (AMR) AF: 0.0115 AC: 176 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00617 AC: 420 AN: 68022

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00710 Hom.: 0

Bravo AF: 0.0107

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.49
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0020
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: rs114968209; hg19: chr2-71827820;