2-71674156-C-T

Position:

• chr2-71674156-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.5785-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,591,058 control chromosomes in the GnomAD database, including 558,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46340 hom., cov: 31)
  • Exomes 𝑓: 0.84 (512354 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.675

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-71674156-C-T is Benign according to our data. Variant chr2-71674156-C-T is described in ClinVar as [Benign]. Clinvar id is 259082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71674156-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5785-41C>T		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.5668-41C>T		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5785-41C>T		intron_variant		1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.5668-41C>T		intron_variant		1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117510 AN: 151952 Hom.: 46341 Cov.: 31

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.766

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.787

GnomAD3 exomes AF: 0.806 AC: 201112 AN: 249436 Hom.: 81719 AF XY: 0.813 AC XY: 109580 AN XY: 134814

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.745

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.712

Gnomad SAS exome AF: 0.797

Gnomad FIN exome AF: 0.865

Gnomad NFE exome AF: 0.859

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.842 AC: 1210948 AN: 1438988 Hom.: 512354 Cov.: 25 AF XY: 0.840 AC XY: 602764 AN XY: 717338

Gnomad4 AFR exome AF: 0.597

Gnomad4 AMR exome AF: 0.748

Gnomad4 ASJ exome AF: 0.805

Gnomad4 EAS exome AF: 0.650

Gnomad4 SAS exome AF: 0.795

Gnomad4 FIN exome AF: 0.863

Gnomad4 NFE exome AF: 0.864

Gnomad4 OTH exome AF: 0.822

GnomAD4 genome AF: 0.773 AC: 117539 AN: 152070 Hom.: 46340 Cov.: 31 AF XY: 0.773 AC XY: 57461 AN XY: 74352

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.766

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.792

Gnomad4 FIN AF: 0.869

Gnomad4 NFE AF: 0.861

Gnomad4 OTH AF: 0.783

Alfa AF: 0.836 Hom.: 74837

Bravo AF: 0.759

Asia WGS AF: 0.710 AC: 2468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Distal myopathy with anterior tibial onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Miyoshi muscular dystrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.60

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: rs2559081; hg19: chr2-71901286;