rs34603128

Variant names:

• chr2-71511857-C-T
• rs34603128
• NM_001130987.2:c.396C>T

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.396C>T​(p.Pro132Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,551,400 control chromosomes in the GnomAD database, including 12,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1677 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10355 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.263
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.47).
• BP6: Variant 2-71511857-C-T is Benign according to our data. Variant chr2-71511857-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 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.396C>T	p.Pro132Pro	synonymous	Exon 5 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.393C>T	p.Pro131Pro	synonymous	Exon 5 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.393C>T	p.Pro131Pro	synonymous	Exon 5 of 56	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.396C>T	p.Pro132Pro	synonymous	Exon 5 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.393C>T	p.Pro131Pro	synonymous	Exon 5 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.393C>T	p.Pro131Pro	synonymous	Exon 5 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21070 AN: 152118 Hom.: 1675 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.104 AC: 16380 AN: 156760 AF XY: 0.102

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0899

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.117 AC: 164029 AN: 1399164 Hom.: 10355 Cov.: 32 AF XY: 0.115 AC XY: 79441 AN XY: 690112

African (AFR) AF: 0.205 AC: 6464 AN: 31592

American (AMR) AF: 0.0932 AC: 3327 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 1697 AN: 25182

East Asian (EAS) AF: 0.00646 AC: 231 AN: 35738

South Asian (SAS) AF: 0.0589 AC: 4664 AN: 79232

European-Finnish (FIN) AF: 0.133 AC: 6564 AN: 49216

Middle Eastern (MID) AF: 0.105 AC: 597 AN: 5690

European-Non Finnish (NFE) AF: 0.124 AC: 133934 AN: 1078800

Other (OTH) AF: 0.113 AC: 6551 AN: 58008

GnomAD4 genome AF: 0.139 AC: 21090 AN: 152236 Hom.: 1677 Cov.: 33 AF XY: 0.137 AC XY: 10181 AN XY: 74444

African (AFR) AF: 0.200 AC: 8303 AN: 41530

American (AMR) AF: 0.121 AC: 1847 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3472

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5182

South Asian (SAS) AF: 0.0505 AC: 244 AN: 4828

European-Finnish (FIN) AF: 0.136 AC: 1440 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8541 AN: 67994

Other (OTH) AF: 0.141 AC: 298 AN: 2112

Alfa AF: 0.130 Hom.: 878

Bravo AF: 0.142

Asia WGS AF: 0.0420 AC: 148 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2B (2)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	2	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.0
DANN	Benign	0.84
PhyloP100		-0.26
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: rs34603128; hg19: chr2-71738987;