rs111935215

chr2-71612621-G-Achr2-71612621-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.4222-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,612,970 control chromosomes in the GnomAD database, including 642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 33)
  • Exomes 𝑓: 0.025 (586 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.696

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=-0.89).
• BP6: Variant 2-71612621-G-A is Benign according to our data. Variant chr2-71612621-G-A is described in ClinVar as [Benign]. Clinvar id is 94319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71612621-G-A is described in Lovd as [Benign]. Variant chr2-71612621-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0247 (3757/152322) while in subpopulation SAS AF= 0.0425 (205/4828). AF 95% confidence interval is 0.0377. There are 56 homozygotes in gnomad4. There are 1815 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.4222-20G>A		intron_variant		ENST00000410020.8
DYSF	NM_003494.4	c.4168-20G>A		intron_variant		ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000258104.8	c.4168-20G>A		intron_variant		1	NM_003494.4	A1
DYSF	ENST00000410020.8	c.4222-20G>A		intron_variant		1	NM_001130987.2	A1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3753 AN: 152204 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0662

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0236 AC: 5920 AN: 250586 Hom.: 108 AF XY: 0.0251 AC XY: 3400 AN XY: 135478

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0731

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0441

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0248 AC: 36185 AN: 1460648 Hom.: 586 Cov.: 31 AF XY: 0.0253 AC XY: 18354 AN XY: 726362

Gnomad4 AFR exome AF: 0.0310

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0752

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0429

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0277

GnomAD4 genome AF: 0.0247 AC: 3757 AN: 152322 Hom.: 56 Cov.: 33 AF XY: 0.0244 AC XY: 1815 AN XY: 74480

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.0662

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0425

Gnomad4 FIN AF: 0.00876

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0301 Hom.: 17

Bravo AF: 0.0249

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	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 provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Miyoshi muscular dystrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Qualitative or quantitative defects of dysferlin Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.12
Dann	Benign	0.49

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: rs111935215; hg19: chr2-71839751; COSMIC: COSV50461912;