rs1553415109

Positions:

• chr2-71668763-C-A
• chr2-71668763-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001130987.2(DYSF):​c.5467C>A​(p.Gln1823Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain C2 7 (size 148) in uniprot entity DYSF_HUMAN there are 37 pathogenic changes around while only 2 benign (95%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5467C>A	p.Gln1823Lys	missense_variant	49/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.5350C>A	p.Gln1784Lys	missense_variant	48/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5467C>A	p.Gln1823Lys	missense_variant	49/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.5350C>A	p.Gln1784Lys	missense_variant	48/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461418 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726964

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.8	.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.71	P;D;P;P;B;P;P;P;P;P;P
Vest4		0.70
MutPred		0.42		.;.;.;.;Gain of ubiquitination at Q1784 (P = 0.0258);.;.;.;.;.;.;
MVP		0.88
MPC		0.44
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.48
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553415109; hg19: chr2-71895893;