rs368577086

Variant names:

• chr2-71549355-C-A
• rs368577086
• NM_003494.4:c.1486C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-71549355-C-A
• chr2-71549355-C-G
• chr2-71549355-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003494.4(DYSF):​c.1486C>A​(p.Pro496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P496A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DYSF NM_003494.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.100
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066660285).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003494.4. 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_003494.4	MANE Plus Clinical	c.1486C>A	p.Pro496Thr	missense	Exon 17 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130987.2	MANE Select	c.1577-1686C>A		intron	N/A	NP_001124459.1	O75923-13
	DYSF	NM_001130982.2		c.1582C>A	p.Pro528Thr	missense	Exon 18 of 56	NP_001124454.1	O75923-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1486C>A	p.Pro496Thr	missense	Exon 17 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409651.5	TSL:1	c.1582C>A	p.Pro528Thr	missense	Exon 18 of 56	ENSP00000386683.1	O75923-8
	DYSF	ENST00000413539.6	TSL:1	c.1579C>A	p.Pro527Thr	missense	Exon 18 of 56	ENSP00000407046.2	O75923-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248706 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460520 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726398

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111276

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.50
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.10
PROVEAN	Benign	0.15	N
REVEL	Benign	0.17
Sift	Benign	0.70	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of phosphorylation at P496 (P = 0.0396)
MVP		0.56
ClinPred		0.067	T
GERP RS		1.4
Varity_R		0.046
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs368577086; hg19: chr2-71776485;