rs145412880

Variant names:

• chr2-71611548-C-T
• rs145412880
• NM_001130987.2:c.4143C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001130987.2(DYSF):​c.4143C>T​(p.Gly1381Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,613,888 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: -1.84

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-71611548-C-T is Benign according to our data. Variant chr2-71611548-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287813.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr2-71611548-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4143C>T	p.Gly1381Gly	synonymous_variant	Exon 38 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4089C>T	p.Gly1363Gly	synonymous_variant	Exon 38 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4143C>T	p.Gly1381Gly	synonymous_variant	Exon 38 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4089C>T	p.Gly1363Gly	synonymous_variant	Exon 38 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152006 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251260 Hom.: 1 AF XY: 0.000405 AC XY: 55 AN XY: 135854

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000801

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000678 AC: 991 AN: 1461882 Hom.: 2 Cov.: 34 AF XY: 0.000652 AC XY: 474 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000864

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152006 Hom.: 0 Cov.: 33 AF XY: 0.000216 AC XY: 16 AN XY: 74224

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000340

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYSF: BP4, BP7 -

Jul 12, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26467025, 18853459) -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi myopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DYSF-related disorder Benign:1

May 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.60

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: rs145412880; hg19: chr2-71838678;