2-71679148-A-C

Variant names:

• chr2-71679148-A-C
• rs17718530
• NM_001130987.2:c.5976A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):​c.5976A>C​(p.Pro1992Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,846 control chromosomes in the GnomAD database, including 46,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1992P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (3819 hom., cov: 31)
  • Exomes 𝑓: 0.24 (42899 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.942
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-71679148-A-C is Benign according to our data. Variant chr2-71679148-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.942 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 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.5976A>C	p.Pro1992Pro	synonymous	Exon 53 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.5859A>C	p.Pro1953Pro	synonymous	Exon 52 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.5973A>C	p.Pro1991Pro	synonymous	Exon 53 of 56	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.5976A>C	p.Pro1992Pro	synonymous	Exon 53 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.5859A>C	p.Pro1953Pro	synonymous	Exon 52 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.5973A>C	p.Pro1991Pro	synonymous	Exon 53 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32596 AN: 151952 Hom.: 3815 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0737

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.210 AC: 52786 AN: 251424 AF XY: 0.216

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0977

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0726

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.237 AC: 345867 AN: 1461774 Hom.: 42899 Cov.: 39 AF XY: 0.237 AC XY: 172049 AN XY: 727192

African (AFR) AF: 0.159 AC: 5325 AN: 33470

American (AMR) AF: 0.105 AC: 4691 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3836 AN: 26134

East Asian (EAS) AF: 0.0745 AC: 2957 AN: 39698

South Asian (SAS) AF: 0.219 AC: 18847 AN: 86248

European-Finnish (FIN) AF: 0.311 AC: 16615 AN: 53412

Middle Eastern (MID) AF: 0.157 AC: 904 AN: 5768

European-Non Finnish (NFE) AF: 0.251 AC: 279644 AN: 1111942

Other (OTH) AF: 0.216 AC: 13048 AN: 60380

GnomAD4 genome AF: 0.214 AC: 32617 AN: 152072 Hom.: 3819 Cov.: 31 AF XY: 0.215 AC XY: 15994 AN XY: 74324

African (AFR) AF: 0.170 AC: 7041 AN: 41484

American (AMR) AF: 0.142 AC: 2174 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 526 AN: 3468

East Asian (EAS) AF: 0.0737 AC: 381 AN: 5172

South Asian (SAS) AF: 0.220 AC: 1059 AN: 4816

European-Finnish (FIN) AF: 0.297 AC: 3137 AN: 10564

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17502 AN: 67960

Other (OTH) AF: 0.200 AC: 423 AN: 2114

Alfa AF: 0.237 Hom.: 12840

Bravo AF: 0.198

Asia WGS AF: 0.181 AC: 629 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.243

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2B (2)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	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	-0.82
CADD	Benign	0.22
DANN	Benign	0.50
PhyloP100		-0.94
Mutation Taster		=95/5	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: rs17718530; hg19: chr2-71906278;