chr2-71569911-A-G

Variant names:

• chr2-71569911-A-G
• rs144636654
• NM_001130987.2:c.2956A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001130987.2(DYSF):​c.2956A>G​(p.Met986Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M986L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-71569911-A-T is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.2956A>G	p.Met986Val	missense_variant	Exon 27 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2902A>G	p.Met968Val	missense_variant	Exon 27 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.2956A>G	p.Met986Val	missense_variant	Exon 27 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.2902A>G	p.Met968Val	missense_variant	Exon 27 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727174

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: 0.0000232

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	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	33
DANN	Benign	0.95
DEOGEN2	Benign	0.31	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	0.099
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.61	.;.;N;.;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.053	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.040	B;B;B;B;B;P;P;B;B;B;B
Vest4		0.70
MutPred		0.47		.;.;Loss of catalytic residue at M968 (P = 0.0076);.;Loss of catalytic residue at M968 (P = 0.0076);.;.;.;.;.;.;
MVP		0.78
MPC		0.20
ClinPred		0.45	T
GERP RS		5.2
Varity_R		0.38
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144636654; hg19: chr2-71797041;