rs121908961

chr2-71667376-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001130987.2(DYSF):c.5318A>G(p.Glu1773Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYSF NM_001130987.2 missense, splice_region
• Scores: Splicing: ADA: 0.1041
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.98

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-71667376-A-G is Pathogenic according to our data. Variant chr2-71667376-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-71667376-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.5318A>G	p.Glu1773Gly	missense_variant, splice_region_variant	48/56	ENST00000410020.8
DYSF	NM_003494.4	c.5201A>G	p.Glu1734Gly	missense_variant, splice_region_variant	47/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.5318A>G	p.Glu1773Gly	missense_variant, splice_region_variant	48/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.5201A>G	p.Glu1734Gly	missense_variant, splice_region_variant	47/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 17, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.046	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.068	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.010	B;B;B;B;B;B;B;B;B;B;P
Vest4		0.56
MutPred		0.38		.;.;.;.;Loss of disorder (P = 0.1038);.;.;.;.;.;.;
MVP		0.87
MPC		0.19
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.37
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908961; hg19: chr2-71894506;