2-71668842-G-A

Position:

• chr2-71668842-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The ENST00000410020.8(DYSF):​c.5546G>A​(p.Arg1849Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYSF ENST00000410020.8 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.40

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000410020.8
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-71668842-G-A is Pathogenic according to our data. Variant chr2-71668842-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71668842-G-A is described in Lovd as [Pathogenic]. Variant chr2-71668842-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5546G>A	p.Arg1849Lys	missense_variant, splice_region_variant	49/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.5429G>A	p.Arg1810Lys	missense_variant, splice_region_variant	48/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5546G>A	p.Arg1849Lys	missense_variant, splice_region_variant	49/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.5429G>A	p.Arg1810Lys	missense_variant, splice_region_variant	48/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459764 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726092

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg1849Lys variant in DYSF (sometimes called p.Gly1802ValfsX17 due to its splicing effect) was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD) (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Arg1849Lys variant in DYSF has been reported in 7 Portuguese individuals with LGMD, including one individual compound heterozygous with this variant and a second variant not reported in ClinVar, c.5657delG (PMID: 20535123). In vitro functional studies with peripheral blood and muscle tissue from 7 unrelated individuals with LGMD and this variant (6 homozygous, 1 heterozygous) provide some evidence that the p.Arg1849Lys variant may impact protein function. Transcript analysis demonstrated an abnormal lack of splicing Exon 49, resulting in a reading frameshift and early termination of the protein (PMID: 20535123). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP3 (Richards 2015). -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 09, 2016

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2023

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1810 of the DYSF protein (p.Arg1810Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 20535123; Invitae). This variant is also known as c.5492G>A and c.5525G>A. ClinVar contains an entry for this variant (Variation ID: 18443). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 49 and introduces a premature termination codon (PMID: 20535123). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	32
DANN	Benign	0.92
DEOGEN2	Benign	0.16	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.82	.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.080	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.92	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0050	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.28
MutPred		0.50		.;.;.;.;Gain of methylation at R1810 (P = 0.0071);.;.;.;.;.;.;
MVP		0.79
MPC		0.15
ClinPred		0.79	D
GERP RS		4.9
Varity_R		0.17
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205084; hg19: chr2-71895972;