rs34211915

chr2-71570632-G-A

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.3119G>A(p.Arg1040Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0213 in 1,614,056 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1040W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (57 hom., cov: 33)
  • Exomes 𝑓: 0.021 (389 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.75

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 (MetaRNN=0.0072483122).
• BP6: Variant 2-71570632-G-A is Benign according to our data. Variant chr2-71570632-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71570632-G-A is described in Lovd as [Likely_benign]. Variant chr2-71570632-G-A is described in Lovd as [Benign]. Variant chr2-71570632-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71570632-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0246 (3746/152310) while in subpopulation AFR AF= 0.0348 (1447/41552). AF 95% confidence interval is 0.0333. There are 57 homozygotes in gnomad4. There are 1826 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.3119G>A	p.Arg1040Gln	missense_variant	29/56	ENST00000410020.8
DYSF	NM_003494.4	c.3065G>A	p.Arg1022Gln	missense_variant	29/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.3119G>A	p.Arg1040Gln	missense_variant	29/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.3065G>A	p.Arg1022Gln	missense_variant	29/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3745 AN: 152196 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0184 AC: 4611 AN: 250548 Hom.: 54 AF XY: 0.0177 AC XY: 2404 AN XY: 135574

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0209 AC: 30594 AN: 1461746 Hom.: 389 Cov.: 33 AF XY: 0.0200 AC XY: 14576 AN XY: 727176

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0232

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0246 AC: 3746 AN: 152310 Hom.: 57 Cov.: 33 AF XY: 0.0245 AC XY: 1826 AN XY: 74472

Gnomad4 AFR AF: 0.0348

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.0243

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0225 Hom.: 84

Bravo AF: 0.0226

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.0332 AC: 146

ESP6500EA AF: 0.0187 AC: 161

ExAC AF: 0.0199 AC: 2414

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0199

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DYSF: PM5, BP4, BS1, BS2 -

Qualitative or quantitative defects of dysferlin Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0072	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.59	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.17	B;P;D;P;D;P;D;D;D;P;B
Vest4		0.61
MPC		0.18
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34211915; hg19: chr2-71797762; COSMIC: COSV50313285;