2-71520900-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_001130987.2(DYSF):c.1145C>T(p.Ala382Val) variant causes a missense change. The variant allele was found at a frequency of 0.000709 in 1,613,988 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A382A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (6 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.89

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 -10 ACMG points.

• PM1: In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 52 pathogenic changes around while only 18 benign (74%) in NM_001130987.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011333644).
• BP6: Variant 2-71520900-C-T is Benign according to our data. Variant chr2-71520900-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520900-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1145C>T	p.Ala382Val	missense_variant	12/56	ENST00000410020.8
DYSF	NM_003494.4	c.1049C>T	p.Ala350Val	missense_variant	11/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.1145C>T	p.Ala382Val	missense_variant	12/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.1049C>T	p.Ala350Val	missense_variant	11/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000899 AC: 226 AN: 251426 Hom.: 1 AF XY: 0.000795 AC XY: 108 AN XY: 135894

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000441 AC: 645 AN: 1461734 Hom.: 6 Cov.: 32 AF XY: 0.000396 AC XY: 288 AN XY: 727168

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74444

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.00363

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00119 AC: 145

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2023	See Variant Classification Assertion Criteria. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 31, 2015

- -

DYSF-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 13, 2019

- -

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.093
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.65	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.42	B;P;P;P;P;P;P;P;P;P;B
Vest4		0.45
MVP		0.80
MPC		0.35
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.073
gMVP		0.32

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: rs115279465; hg19: chr2-71748030;