2-71679173-C-T

Position:

• chr2-71679173-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001130987.2(DYSF):​c.6001C>T​(p.Gln2001Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYSF NM_001130987.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-71679173-C-T is Pathogenic according to our data. Variant chr2-71679173-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 419655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71679173-C-T is described in Lovd as [Pathogenic]. Variant chr2-71679173-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.6001C>T	p.Gln2001Ter	stop_gained	53/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.5884C>T	p.Gln1962Ter	stop_gained	52/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.6001C>T	p.Gln2001Ter	stop_gained	53/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.5884C>T	p.Gln1962Ter	stop_gained	52/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2018	The Q1962X nonsense variant in the DYSF gene has been reported previously in two brothers with dysferlinopathywho were compound heterozygous for Q1962X and another DYSF variant (Rosales et al.,2010). One study indicated Q1962X induced a large splicing change, though in silico algorithms do notpredict Q1962X affects splicing (Xiong et al., 2014). This variant is predicted to cause loss of normalprotein function either through protein truncation or nonsense-mediated mRNA decay. The Q1962Xvariant was not observed in approximately 6500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. Weinterpret Q1962X as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 04, 2021	- -

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

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jul 28, 2017

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 419655). This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 20544924). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1962*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
Vest4		0.90
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064794020; hg19: chr2-71906303;