rs61746816

Positions:

• chr2-71613335-C-A
• chr2-71613335-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130987.2(DYSF):​c.4389C>A​(p.Asp1463Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense, splice_region
• Scores: Splicing: ADA: 0.001092
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19013578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4389C>A	p.Asp1463Glu	missense_variant, splice_region_variant	40/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4335C>A	p.Asp1445Glu	missense_variant, splice_region_variant	40/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4389C>A	p.Asp1463Glu	missense_variant, splice_region_variant	40/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4335C>A	p.Asp1445Glu	missense_variant, splice_region_variant	40/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248726 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460288 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	T;D;D;T;T;T;T;D;D;D;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.1	.;.;L;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.55	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.43	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.95	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.94	P;B;B;B;B;D;D;B;B;B;P
Vest4		0.58
MutPred		0.38		.;.;Gain of solvent accessibility (P = 0.007);.;Gain of solvent accessibility (P = 0.007);.;.;.;.;.;.;
MVP		0.71
MPC		0.16
ClinPred		0.061	T
GERP RS		-3.6
Varity_R		0.042
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.59		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61746816; hg19: chr2-71840465;