rs115849497

Variant names:

• chr2-71553148-G-A
• rs115849497
• NM_001130987.2:c.1944G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-71553148-G-A
• chr2-71553148-G-C
• chr2-71553148-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001130987.2(DYSF):​c.1944G>A​(p.Pro648Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,074 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P648P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -4.24
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-71553148-G-A is Benign according to our data. Variant chr2-71553148-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94283.
• BP7: Synonymous conserved (PhyloP=-4.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00747 (1137/152268) while in subpopulation AFR AF = 0.0246 (1021/41548). AF 95% confidence interval is 0.0233. There are 13 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1944G>A	p.Pro648Pro	synonymous	Exon 20 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.1890G>A	p.Pro630Pro	synonymous	Exon 20 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.1941G>A	p.Pro647Pro	synonymous	Exon 20 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.1944G>A	p.Pro648Pro	synonymous	Exon 20 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1890G>A	p.Pro630Pro	synonymous	Exon 20 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.1941G>A	p.Pro647Pro	synonymous	Exon 20 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1133 AN: 152150 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00234 AC: 587 AN: 251314 AF XY: 0.00200

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00105 AC: 1539 AN: 1461806 Hom.: 16 Cov.: 34 AF XY: 0.000990 AC XY: 720 AN XY: 727196

African (AFR) AF: 0.0243 AC: 812 AN: 33480

American (AMR) AF: 0.00273 AC: 122 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53332

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.000393 AC: 437 AN: 1112012

Other (OTH) AF: 0.00195 AC: 118 AN: 60396

GnomAD4 genome AF: 0.00747 AC: 1137 AN: 152268 Hom.: 13 Cov.: 33 AF XY: 0.00736 AC XY: 548 AN XY: 74462

African (AFR) AF: 0.0246 AC: 1021 AN: 41548

American (AMR) AF: 0.00491 AC: 75 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68016

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00500 Hom.: 4

Bravo AF: 0.00878

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.77
DANN	Benign	0.65
PhyloP100		-4.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115849497; hg19: chr2-71780278;