rs59915619

chr2-71574310-G-Achr2-71574310-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001130987.2(DYSF):c.3341G>A(p.Arg1114His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,092 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1114S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (8 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.60

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009912878).
• BP6: Variant 2-71574310-G-A is Benign according to our data. Variant chr2-71574310-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128947.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr2-71574310-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00556 (847/152340) while in subpopulation AFR AF= 0.0196 (816/41588). AF 95% confidence interval is 0.0185. There are 15 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.3341G>A	p.Arg1114His	missense_variant	30/56	ENST00000410020.8
DYSF	NM_003494.4	c.3287G>A	p.Arg1096His	missense_variant	30/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.3341G>A	p.Arg1114His	missense_variant	30/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.3287G>A	p.Arg1096His	missense_variant	30/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 838 AN: 152222 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00148 AC: 372 AN: 251210 Hom.: 6 AF XY: 0.00109 AC XY: 148 AN XY: 135770

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000555 AC: 812 AN: 1461752 Hom.: 8 Cov.: 33 AF XY: 0.000487 AC XY: 354 AN XY: 727172

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152340 Hom.: 15 Cov.: 33 AF XY: 0.00564 AC XY: 420 AN XY: 74486

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0303 Hom.: 3182

Bravo AF: 0.00630

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 22, 2021	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 19, 2018

- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 04, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.59
MVP		0.97
MPC		0.72
ClinPred		0.064	T
GERP RS		5.6
Varity_R		0.57
gMVP		0.63

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: rs59915619; hg19: chr2-71801440;