2-71503254-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Moderate BP6_Moderate

The NM_001130987.2(DYSF):c.280G>C(p.Ala94Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A94T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.397

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 1 (size 100) in uniprot entity DYSF_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20434687).
• BP6: Variant 2-71503254-G-C is Benign according to our data. Variant chr2-71503254-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 538625.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.280G>C	p.Ala94Pro	missense_variant	4/56	ENST00000410020.8
DYSF	NM_003494.4	c.277G>C	p.Ala93Pro	missense_variant	4/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.280G>C	p.Ala94Pro	missense_variant	4/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.277G>C	p.Ala93Pro	missense_variant	4/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251460 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

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.: 32

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Qualitative or quantitative defects of dysferlin Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	0.0047
Eigen_PC	Benign	0.0089
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L;L;L;L;L;.;.;.;.;.;.
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.039	D;D;T;D;T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.92	P;P;D;P;P;P;B;P;P;P;P
Vest4		0.35
MutPred		0.44		Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);.;.;.;.;.;.;
MVP		0.77
MPC		0.44
ClinPred		0.17	T
GERP RS		2.8
Varity_R		0.55
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs759171890; hg19: chr2-71730384;