rs746663568

chr2-71682669-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_001130987.2(DYSF):c.6313G>A(p.Ala2105Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2105V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.37

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-71682669-G-A is Pathogenic according to our data. Variant chr2-71682669-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}. Variant chr2-71682669-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71682669-G-A is described in Lovd as [Pathogenic]. Variant chr2-71682669-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.28245357).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.6313G>A	p.Ala2105Thr	missense_variant	55/56	ENST00000410020.8
DYSF	NM_003494.4	c.6196G>A	p.Ala2066Thr	missense_variant	54/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.6313G>A	p.Ala2105Thr	missense_variant	55/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.6196G>A	p.Ala2066Thr	missense_variant	54/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250566 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135468

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727136

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 10, 2023

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2066 of the DYSF protein (p.Ala2066Thr). This variant is present in population databases (rs746663568, gnomAD 0.002%). This missense change has been observed in individual(s) with dysferlinopathy and/or limb girdle muscular dystrophy (PMID: 21522182, 27066573, 32400077, 32528171, 34559919; Invitae). This variant is also known as c.6313G>A, p.A2105T. ClinVar contains an entry for this variant (Variation ID: 557110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYSF protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 14, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.074
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.099	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.086	B;B;B;P;B;P;P;B;P;P;B
Vest4		0.56
MutPred		0.39		.;.;.;.;Loss of catalytic residue at A2066 (P = 0.0891);.;.;.;.;.;.;
MVP		0.78
MPC		0.15
ClinPred		0.67	D
GERP RS		4.3
Varity_R		0.10
gMVP		0.68

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: rs746663568; hg19: chr2-71909799;