2-71568318-G-T

Position:

• chr2-71568318-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Very_Strong PM2 PP3_Strong

The ENST00000410020.8(DYSF):​c.2844G>T​(p.Trp948Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF ENST00000410020.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

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 Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript ENST00000410020.8 (DYSF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 167021
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.2844G>T	p.Trp948Cys	missense_variant	26/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2790G>T	p.Trp930Cys	missense_variant	26/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.2844G>T	p.Trp948Cys	missense_variant	26/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.2790G>T	p.Trp930Cys	missense_variant	26/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	.;.;M;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-12	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.98
MutPred		0.92		.;.;Loss of sheet (P = 0.0084);.;Loss of sheet (P = 0.0084);.;.;.;.;.;.;
MVP		0.93
MPC		0.82
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.94

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: rs727503910; hg19: chr2-71795448; COSMIC: COSV50267911; COSMIC: COSV50267911;