rs7573406

Variant names:

• chr2-71644058-C-G
• rs7573406
• NM_001130987.2:c.4621C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-71644058-C-G
• chr2-71644058-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001130987.2(DYSF):​c.4621C>G​(p.Leu1541Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1541P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26521677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4621C>G	p.Leu1541Val	missense_variant	Exon 42 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4504C>G	p.Leu1502Val	missense_variant	Exon 41 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4621C>G	p.Leu1541Val	missense_variant	Exon 42 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4504C>G	p.Leu1502Val	missense_variant	Exon 41 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457266 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724326

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33440

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44230

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25966

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39658

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85092

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53172

Gnomad4 NFE exome AF: 9.01e-7 AC: 1 AN: 1109734

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60246

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.60	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.7	.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;P;B;D;D;D;D;D;D;D;D
Vest4		0.50
MutPred		0.44		.;.;.;.;Gain of methylation at K1503 (P = 0.0425);.;.;.;.;.;.;
MVP		0.73
MPC		0.40
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.61
Mutation Taster		=49/51	disease causing

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: rs7573406; hg19: chr2-71871188;