chr2-71528250-A-G

Position:

• chr2-71528250-A-G

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.1277-48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,536,098 control chromosomes in the GnomAD database, including 497,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50265 hom., cov: 32)
  • Exomes 𝑓: 0.80 (447632 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0510

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=-0.9).
• BP6: Variant 2-71528250-A-G is Benign according to our data. Variant chr2-71528250-A-G is described in ClinVar as [Benign]. Clinvar id is 259065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71528250-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1277-48A>G		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1181-48A>G		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.1181-48A>G		intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.1277-48A>G		intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121834 AN: 152072 Hom.: 50212 Cov.: 32

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.806

GnomAD3 exomes AF: 0.733 AC: 166725 AN: 227464 Hom.: 64909 AF XY: 0.731 AC XY: 89120 AN XY: 121940

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.685

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.589

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.832

Gnomad OTH exome AF: 0.774

GnomAD4 exome AF: 0.795 AC: 1100315 AN: 1383908 Hom.: 447632 Cov.: 20 AF XY: 0.790 AC XY: 545399 AN XY: 690732

Gnomad4 AFR exome AF: 0.892

Gnomad4 AMR exome AF: 0.697

Gnomad4 ASJ exome AF: 0.859

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.785

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.779

GnomAD4 genome AF: 0.801 AC: 121948 AN: 152190 Hom.: 50265 Cov.: 32 AF XY: 0.788 AC XY: 58659 AN XY: 74424

Gnomad4 AFR AF: 0.887

Gnomad4 AMR AF: 0.732

Gnomad4 ASJ AF: 0.859

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.777

Gnomad4 NFE AF: 0.828

Gnomad4 OTH AF: 0.802

Alfa AF: 0.823 Hom.: 10640

Bravo AF: 0.803

Asia WGS AF: 0.429 AC: 1496 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	-0.90
CADD	Benign	5.3
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4852800; hg19: chr2-71755380; COSMIC: COSV50340320;