rs34836829

Variant names:

• chr2-71568330-G-A
• rs34836829
• NM_001130987.2:c.2856G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-71568330-G-A
• chr2-71568330-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130987.2(DYSF):​c.2856G>A​(p.Pro952Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,614,078 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (88 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1278 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.77
• 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: 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=-0.66).
• BP6: Variant 2-71568330-G-A is Benign according to our data. Variant chr2-71568330-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3825/152286) while in subpopulation NFE AF = 0.0385 (2616/68018). AF 95% confidence interval is 0.0372. There are 88 homozygotes in GnomAd4. There are 1797 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 88 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.2856G>A	p.Pro952Pro	synonymous	Exon 26 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.2802G>A	p.Pro934Pro	synonymous	Exon 26 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.2853G>A	p.Pro951Pro	synonymous	Exon 26 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.2856G>A	p.Pro952Pro	synonymous	Exon 26 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.2802G>A	p.Pro934Pro	synonymous	Exon 26 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.2853G>A	p.Pro951Pro	synonymous	Exon 26 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3826 AN: 152168 Hom.: 88 Cov.: 33

Gnomad AFR AF: 0.00663

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0278 AC: 6968 AN: 250236 AF XY: 0.0294

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0667

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0367

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0386 AC: 56414 AN: 1461792 Hom.: 1278 Cov.: 36 AF XY: 0.0385 AC XY: 28007 AN XY: 727194

African (AFR) AF: 0.00541 AC: 181 AN: 33478

American (AMR) AF: 0.0112 AC: 503 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0684 AC: 1789 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0379 AC: 3266 AN: 86256

European-Finnish (FIN) AF: 0.0187 AC: 999 AN: 53398

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5766

European-Non Finnish (NFE) AF: 0.0425 AC: 47205 AN: 1111944

Other (OTH) AF: 0.0387 AC: 2340 AN: 60392

GnomAD4 genome AF: 0.0251 AC: 3825 AN: 152286 Hom.: 88 Cov.: 33 AF XY: 0.0241 AC XY: 1797 AN XY: 74464

African (AFR) AF: 0.00661 AC: 275 AN: 41574

American (AMR) AF: 0.0182 AC: 279 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0348 AC: 168 AN: 4822

European-Finnish (FIN) AF: 0.0152 AC: 162 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0385 AC: 2616 AN: 68018

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0345 Hom.: 74

Bravo AF: 0.0244

Asia WGS AF: 0.00895 AC: 31 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)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.59
DANN	Benign	0.71
PhyloP100		-4.8
Mutation Taster		=96/4	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: rs34836829; hg19: chr2-71795460; COSMIC: COSV50309232; COSMIC: COSV50309232;