chr2-71598577-C-T

Position:

• chr2-71598577-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001130987.2(DYSF):​c.3588C>T​(p.Ile1196=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,614,198 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts 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. I1196I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (53 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: -0.617

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.

• BP6: Variant 2-71598577-C-T is Benign according to our data. Variant chr2-71598577-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94307.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=4}. Variant chr2-71598577-C-T is described in Lovd as [Benign]. Variant chr2-71598577-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.3588C>T	p.Ile1196=	synonymous_variant	33/56	ENST00000410020.8
DYSF	NM_003494.4	c.3534C>T	p.Ile1178=	synonymous_variant	33/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.3588C>T	p.Ile1196=	synonymous_variant	33/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.3534C>T	p.Ile1178=	synonymous_variant	33/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152218 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00948

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00666 AC: 1673 AN: 251142 Hom.: 7 AF XY: 0.00678 AC XY: 920 AN XY: 135782

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00827

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00787 AC: 11498 AN: 1461862 Hom.: 53 Cov.: 32 AF XY: 0.00790 AC XY: 5747 AN XY: 727226

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00938

Gnomad4 NFE exome AF: 0.00899

Gnomad4 OTH exome AF: 0.00679

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152336 Hom.: 6 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74504

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00828

Gnomad4 NFE AF: 0.00948

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00797 Hom.: 7

Bravo AF: 0.00560

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00759

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DYSF: BS2 -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Miyoshi myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Miyoshi muscular dystrophy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.3
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79899601; hg19: chr2-71825707;