rs72827543

Positions:

• chr2-71555922-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130987.2(DYSF):​c.2110-43G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,490,578 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 33)
  • Exomes 𝑓: 0.020 (315 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24

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=-0.65).
• BP6: Variant 2-71555922-G-T is Benign according to our data. Variant chr2-71555922-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 259070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71555922-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2607/152326) while in subpopulation NFE AF= 0.0254 (1727/68008). AF 95% confidence interval is 0.0244. There are 33 homozygotes in gnomad4. There are 1285 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.2110-43G>T		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2056-43G>T		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.2056-43G>T		intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.2110-43G>T		intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2607 AN: 152208 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0135 AC: 2093 AN: 154846 Hom.: 27 AF XY: 0.0131 AC XY: 1070 AN XY: 81692

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.00787

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000175

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0198 AC: 26474 AN: 1338252 Hom.: 315 Cov.: 22 AF XY: 0.0191 AC XY: 12686 AN XY: 663458

Gnomad4 AFR exome AF: 0.00704

Gnomad4 AMR exome AF: 0.00736

Gnomad4 ASJ exome AF: 0.00751

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000154

Gnomad4 FIN exome AF: 0.0284

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0171 AC: 2607 AN: 152326 Hom.: 33 Cov.: 33 AF XY: 0.0173 AC XY: 1285 AN XY: 74484

Gnomad4 AFR AF: 0.00803

Gnomad4 AMR AF: 0.00999

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0234 Hom.: 15

Bravo AF: 0.0143

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.096
DANN	Benign	0.57

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: rs72827543; hg19: chr2-71783052;