rs199649417

Positions:

• chr2-71669174-C-A
• chr2-71669174-C-T

Variant summary

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

The NM_001130987.2(DYSF):​c.5609C>A​(p.Thr1870Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T1870M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.26

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.5609C>A	p.Thr1870Lys	missense_variant	50/56	ENST00000410020.8
DYSF	NM_003494.4	c.5492C>A	p.Thr1831Lys	missense_variant	49/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.5609C>A	p.Thr1870Lys	missense_variant	50/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.5492C>A	p.Thr1831Lys	missense_variant	49/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.60
MutPred		0.42		.;.;.;.;Gain of solvent accessibility (P = 0.0156);.;.;.;.;.;.;
MVP		0.90
MPC		0.71
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.89
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199649417; hg19: chr2-71896304;