2-71611467-C-G

Position:

• chr2-71611467-C-G

Variant summary

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

The NM_001130987.2(DYSF):​c.4062C>G​(p.Ile1354Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1354I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354

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 4 ACMG points.

• PM1: In a domain C2 5 (size 128) in uniprot entity DYSF_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) 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.4062C>G	p.Ile1354Met	missense_variant, splice_region_variant	38/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4008C>G	p.Ile1336Met	missense_variant, splice_region_variant	38/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4062C>G	p.Ile1354Met	missense_variant, splice_region_variant	38/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4008C>G	p.Ile1336Met	missense_variant, splice_region_variant	38/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;.;.;.;D;.;.;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	.;.;M;.;M;.;.;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.38	B;B;B;B;P;B;P;P;P;B;B
Vest4		0.63
MutPred		0.49		.;.;Gain of MoRF binding (P = 0.0775);.;Gain of MoRF binding (P = 0.0775);.;.;.;.;.;.;
MVP		0.62
MPC		0.48
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.38
gMVP		0.72

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: rs2303606; hg19: chr2-71838597;