rs147056383

Positions:

• chr2-71660641-G-A
• chr2-71660641-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000410020.8(DYSF):​c.4993G>A​(p.Val1665Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000247 in 1,613,842 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1665V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: DYSF ENST00000410020.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:8
• Conservation: PhyloP100: 4.27

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01881209).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4993G>A	p.Val1665Ile	missense_variant	45/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4876G>A	p.Val1626Ile	missense_variant	44/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4993G>A	p.Val1665Ile	missense_variant	45/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.4876G>A	p.Val1626Ile	missense_variant	44/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00981

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251312 Hom.: 0 AF XY: 0.000670 AC XY: 91 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00963

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461500 Hom.: 3 Cov.: 31 AF XY: 0.000242 AC XY: 176 AN XY: 727066

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00703

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74494

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00983

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000573 Hom.: 3

Bravo AF: 0.000461

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Pathogenic, no assertion criteria provided	reference population	Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology	Jul 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2020	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DYSF: BS1 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2023	Variant summary: DYSF c.4876G>A (p.Val1626Ile) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251312 control chromosomes, predominantly at a frequency of 0.0096 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. It has also been reported at a frequency of 0.0044 in control individuals of Japanese ancestry in the Japanese Whole Genome Reference Panel (ToMMo 38KJPN), including 3 homozygotes. c.4876G>A has been reported in the literature in individuals of East Asian ancestry affected with or suspected of Limb-Girdle Muscular Dystrophy/Dysferlinopathy, without strong evidence for pathogenicity, including one case where it was found in cis with a pathogenic variant, providing supporting evidence for a benign role (e.g. Yu_2017, Liu_2018, Zhong_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as benign (n=1)/likely benign (n=4), two classified the variant as VUS, and one as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2017	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 02, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

Qualitative or quantitative defects of dysferlin Uncertain:1 Benign:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

DYSF-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.42	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.022	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.33
MVP		0.54
MPC		0.12
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.26

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: rs147056383; hg19: chr2-71887771; COSMIC: COSV50284702;