2-71513880-A-T

Variant names:

• chr2-71513880-A-T
• NM_001130987.2:c.718A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001130987.2(DYSF):​c.718A>T​(p.Thr240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.913

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.

• PM1: In a domain C2 2 (size 118) in uniprot entity DYSF_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041870296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.718A>T	p.Thr240Ser	missense_variant	Exon 7 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.622A>T	p.Thr208Ser	missense_variant	Exon 6 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.718A>T	p.Thr240Ser	missense_variant	Exon 7 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.622A>T	p.Thr208Ser	missense_variant	Exon 6 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.85
DANN	Benign	0.25
DEOGEN2	Benign	0.14	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.042	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	.;.;N;.;N;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.060	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.45	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.68	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.15
MutPred		0.26		.;.;Loss of glycosylation at T208 (P = 0.0238);.;Loss of glycosylation at T208 (P = 0.0238);.;.;.;.;.;.;
MVP		0.43
MPC		0.13
ClinPred		0.015	T
GERP RS		-5.8
Varity_R		0.016
gMVP		0.14

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: chr2-71741010;