2-71511847-G-C

Variant names:

• chr2-71511847-G-C
• NM_001130987.2:c.386G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001130987.2(DYSF):​c.386G>C​(p.Gly129Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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. G129E) 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: 8.15

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-71511847-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.386G>C	p.Gly129Ala	missense_variant	Exon 5 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.383G>C	p.Gly128Ala	missense_variant	Exon 5 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.386G>C	p.Gly129Ala	missense_variant	Exon 5 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.383G>C	p.Gly128Ala	missense_variant	Exon 5 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.0	L;L;L;L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.033	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.54
MutPred		0.17		Gain of glycosylation at P131 (P = 0.229);Gain of glycosylation at P131 (P = 0.229);Gain of glycosylation at P131 (P = 0.229);Gain of glycosylation at P131 (P = 0.229);Gain of glycosylation at P131 (P = 0.229);.;.;.;.;.;.;
MVP		0.83
MPC		0.17
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.28
gMVP		0.35

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: chr2-71738977;