chr2-71682692-C-T

Variant names:

• chr2-71682692-C-T
• rs2559082
• NM_001130987.2:c.6321+15C>T

Variant summary

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

The ENST00000410020.8(DYSF):​c.6321+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,611,110 control chromosomes in the GnomAD database, including 38,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3171 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35555 hom.)
• Consequence: DYSF ENST00000410020.8 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.07
• Publications: 7 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 2-71682692-C-T is Benign according to our data. Variant chr2-71682692-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000410020.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.6321+15C>T		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.6204+15C>T		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.6318+15C>T		intron	N/A	NP_001124453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.6321+15C>T		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.6204+15C>T		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.6318+15C>T		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29562 AN: 151902 Hom.: 3165 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0844

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.201 AC: 48904 AN: 243902 AF XY: 0.208

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0855

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.217 AC: 316114 AN: 1459090 Hom.: 35555 Cov.: 35 AF XY: 0.218 AC XY: 158119 AN XY: 725622

African (AFR) AF: 0.127 AC: 4244 AN: 33412

American (AMR) AF: 0.107 AC: 4733 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4317 AN: 26102

East Asian (EAS) AF: 0.0945 AC: 3741 AN: 39576

South Asian (SAS) AF: 0.232 AC: 19939 AN: 85988

European-Finnish (FIN) AF: 0.293 AC: 15619 AN: 53220

Middle Eastern (MID) AF: 0.183 AC: 1053 AN: 5766

European-Non Finnish (NFE) AF: 0.225 AC: 250172 AN: 1110460

Other (OTH) AF: 0.204 AC: 12296 AN: 60294

GnomAD4 genome AF: 0.195 AC: 29588 AN: 152020 Hom.: 3171 Cov.: 32 AF XY: 0.196 AC XY: 14568 AN XY: 74306

African (AFR) AF: 0.133 AC: 5529 AN: 41460

American (AMR) AF: 0.147 AC: 2242 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 577 AN: 3466

East Asian (EAS) AF: 0.0842 AC: 434 AN: 5154

South Asian (SAS) AF: 0.229 AC: 1101 AN: 4818

European-Finnish (FIN) AF: 0.284 AC: 2998 AN: 10570

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15971 AN: 67958

Other (OTH) AF: 0.205 AC: 434 AN: 2112

Alfa AF: 0.210 Hom.: 4051

Bravo AF: 0.178

Asia WGS AF: 0.189 AC: 654 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)
-	-	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	-0.89
CADD	Benign	0.61
DANN	Benign	0.45
PhyloP100		-1.1
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: rs2559082; hg19: chr2-71909822; COSMIC: COSV50340743;