2-71454006-G-C

Variant names:

• chr2-71454006-G-C
• NM_003494.4:c.8G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_003494.4(DYSF):​c.8G>C​(p.Arg3Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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_003494.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.17

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]

ENSG00000289327 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain C2 1 (size 100) in uniprot entity DYSF_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003494.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_003494.4	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

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	0.88
BayesDel_addAF	Benign	0.0084	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.65	.;.;.;.;D
Eigen	Benign	-0.010
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.0	L;L;L;L;L
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.076	T;T;T;T;T
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.15	B;B;B;B;B
Vest4		0.66
MutPred		0.75		Gain of catalytic residue at V4 (P = 0.0716);Gain of catalytic residue at V4 (P = 0.0716);Gain of catalytic residue at V4 (P = 0.0716);Gain of catalytic residue at V4 (P = 0.0716);Gain of catalytic residue at V4 (P = 0.0716);
MVP		0.80
ClinPred		0.73	D
GERP RS		4.1
Varity_R		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-71681136;