2-71511865-C-A

Variant names:

• chr2-71511865-C-A
• rs773837400
• NM_001130987.2:c.404C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130987.2(DYSF):​c.404C>A​(p.Pro135Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. P135L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17674097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.404C>A	p.Pro135Gln	missense_variant	Exon 5 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.401C>A	p.Pro134Gln	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.404C>A	p.Pro135Gln	missense_variant	Exon 5 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.401C>A	p.Pro134Gln	missense_variant	Exon 5 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399366 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690182

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: 0.00

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	Benign	0.099
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.23	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.29	N;N;N;N;N;.;.;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.84	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.27	B;B;B;P;B;P;B;B;B;P;B
Vest4		0.26
MutPred		0.34		Loss of catalytic residue at P134 (P = 0.0095);Loss of catalytic residue at P134 (P = 0.0095);Loss of catalytic residue at P134 (P = 0.0095);Loss of catalytic residue at P134 (P = 0.0095);Loss of catalytic residue at P134 (P = 0.0095);.;.;.;.;.;.;
MVP		0.72
MPC		0.26
ClinPred		0.57	D
GERP RS		4.6
Varity_R		0.072
gMVP		0.24

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: rs773837400; hg19: chr2-71738995;