chr2-71656164-C-G

Position:

• chr2-71656164-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4512C>G p.(Val1504=) variant in DYSF, which is also known as NM_001130987.2: c.4629C>G p.(Val1543=), is a synonymous (silent) variant that is not expected to change the amino acid sequence. The filtering allele frequency for this variant is 0.001985 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2286/1111986 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). While this variant affects the first amino acid of exon 42 and so is located in a splice region (BP7 not met), the SpliceAI score is 0, which is less than the LGMD VCEP threshold of 0.05 (BP4). This variant has been identified in a patient with a clinical suspicion of LGMD but as a single hit in an individual with an alternative molecular diagnosis (LOVD Individual #00220067). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA245628/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: DYSF NM_001130987.2 splice_region, synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:5
• Conservation: PhyloP100: 2.18

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 Likely_benign. Variant got -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4629C>G	p.Val1543Val	splice_region_variant, synonymous_variant	43/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4512C>G	p.Val1504Val	splice_region_variant, synonymous_variant	42/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4629C>G	p.Val1543Val	splice_region_variant, synonymous_variant	43/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4512C>G	p.Val1504Val	splice_region_variant, synonymous_variant	42/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000815 AC: 205 AN: 251476 Hom.: 0 AF XY: 0.000853 AC XY: 116 AN XY: 135912

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00164 AC: 2402 AN: 1461844 Hom.: 6 Cov.: 31 AF XY: 0.00154 AC XY: 1119 AN XY: 727228

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152130 Hom.: 1 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74322

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00130

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs142483266; hg19: chr2-71883294; COSMIC: COSV50595087;