rs34999029

chr2-71513767-C-Achr2-71513767-C-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.605C>A(p.Ala202Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,130 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. A202V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0097 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (134 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.39

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=0.0052174926).
• BP6: Variant 2-71513767-C-A is Benign according to our data. Variant chr2-71513767-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94334.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=2}. Variant chr2-71513767-C-A is described in Lovd as [Likely_benign]. Variant chr2-71513767-C-A is described in Lovd as [Pathogenic]. Variant chr2-71513767-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0124 (18138/1461844) while in subpopulation MID AF= 0.0245 (141/5750). AF 95% confidence interval is 0.0212. There are 134 homozygotes in gnomad4_exome. There are 8810 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.605C>A	p.Ala202Glu	missense_variant	7/56	ENST00000410020.8
DYSF	NM_003494.4	c.509C>A	p.Ala170Glu	missense_variant	6/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.605C>A	p.Ala202Glu	missense_variant	7/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.509C>A	p.Ala170Glu	missense_variant	6/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1472 AN: 152168 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0101 AC: 2546 AN: 251252 Hom.: 16 AF XY: 0.0102 AC XY: 1380 AN XY: 135816

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00372

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0124 AC: 18138 AN: 1461844 Hom.: 134 Cov.: 32 AF XY: 0.0121 AC XY: 8810 AN XY: 727216

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00680

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00966 AC: 1471 AN: 152286 Hom.: 9 Cov.: 32 AF XY: 0.00901 AC XY: 671 AN XY: 74464

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00894

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0126 Hom.: 25

Bravo AF: 0.00943

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.00977 AC: 1186

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0167

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

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)	Mar 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2017	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ala202Glu in exon 7 of DYSF: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (132/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34999029). -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DYSF: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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	Invitae	Jan 31, 2024	- -

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
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Benign	0.92
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.85	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0052	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.70	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.30
MPC		0.17
ClinPred		0.016	T
GERP RS		3.5
Varity_R		0.057
gMVP		0.19

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: rs34999029; hg19: chr2-71740897;