rs35982795

Variant names:

• chr2-71526357-C-T
• rs35982795
• NM_001130987.2:c.1276+11C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-71526357-C-T
• chr2-71526357-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.1276+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,473,386 control chromosomes in the GnomAD database, including 14,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1714 hom., cov: 31)
  • Exomes 𝑓: 0.14 (13274 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.83
• Publications: 4 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-71526357-C-T is Benign according to our data. Variant chr2-71526357-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 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.1276+11C>T		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.1180+11C>T		intron	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1273+11C>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.1276+11C>T		intron	N/A	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1180+11C>T		intron	N/A	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1273+11C>T		intron	N/A	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.150 AC: 21695 AN: 145092 Hom.: 1712 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.116 AC: 28744 AN: 247926 AF XY: 0.117

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0737

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.00349

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.142 AC: 189023 AN: 1328178 Hom.: 13274 Cov.: 36 AF XY: 0.141 AC XY: 93290 AN XY: 659506

African (AFR) AF: 0.218 AC: 6544 AN: 30044

American (AMR) AF: 0.0878 AC: 3545 AN: 40358

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 2788 AN: 20860

East Asian (EAS) AF: 0.00424 AC: 104 AN: 24510

South Asian (SAS) AF: 0.0920 AC: 7815 AN: 84900

European-Finnish (FIN) AF: 0.149 AC: 6184 AN: 41372

Middle Eastern (MID) AF: 0.156 AC: 793 AN: 5086

European-Non Finnish (NFE) AF: 0.149 AC: 153715 AN: 1029662

Other (OTH) AF: 0.147 AC: 7535 AN: 51386

GnomAD4 genome AF: 0.149 AC: 21705 AN: 145208 Hom.: 1714 Cov.: 31 AF XY: 0.147 AC XY: 10364 AN XY: 70704

African (AFR) AF: 0.199 AC: 7947 AN: 39994

American (AMR) AF: 0.122 AC: 1789 AN: 14632

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 354 AN: 3414

East Asian (EAS) AF: 0.00660 AC: 28 AN: 4244

South Asian (SAS) AF: 0.0878 AC: 361 AN: 4112

European-Finnish (FIN) AF: 0.126 AC: 1179 AN: 9338

Middle Eastern (MID) AF: 0.107 AC: 31 AN: 290

European-Non Finnish (NFE) AF: 0.144 AC: 9567 AN: 66276

Other (OTH) AF: 0.147 AC: 298 AN: 2034

Alfa AF: 0.131 Hom.: 286

Bravo AF: 0.145

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Distal myopathy with anterior tibial onset (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	-	1	Miyoshi myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	23
DANN	Benign	0.62
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35982795; hg19: chr2-71753487; COSMIC: COSV50612274;