2-71526286-G-C

Position:

• chr2-71526286-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_001130987.2(DYSF):​c.1216G>C​(p.Val406Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,614,228 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. V406I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (75 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.15

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.

• PM1: In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 52 pathogenic changes around while only 18 benign (74%) in NM_001130987.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-71526286-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.007504314).
• BP6: Variant 2-71526286-G-C is Benign according to our data. Variant chr2-71526286-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94264.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, Uncertain_significance=1}. Variant chr2-71526286-G-C is described in Lovd as [Likely_benign]. Variant chr2-71526286-G-C is described in Lovd as [Pathogenic].
• 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.1216G>C	p.Val406Leu	missense_variant	13/56	ENST00000410020.8
DYSF	NM_003494.4	c.1120G>C	p.Val374Leu	missense_variant	12/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.1216G>C	p.Val406Leu	missense_variant	13/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.1120G>C	p.Val374Leu	missense_variant	12/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 926 AN: 152226 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00549 AC: 1380 AN: 251414 Hom.: 9 AF XY: 0.00565 AC XY: 768 AN XY: 135876

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.00869

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00852 AC: 12454 AN: 1461884 Hom.: 75 Cov.: 32 AF XY: 0.00832 AC XY: 6048 AN XY: 727244

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.00781

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.00608 AC: 926 AN: 152344 Hom.: 6 Cov.: 33 AF XY: 0.00546 AC XY: 407 AN XY: 74488

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00848

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00578

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00567 AC: 688

EpiCase AF: 0.00971

EpiControl AF: 0.00954

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DYSF: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -

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	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2016	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0075	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.97	.;.;L;.;L;.;.;.;.;.;.
MutationTaster	Benign	0.77	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.092	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.15
MutPred		0.72		.;.;Gain of disorder (P = 0.1116);.;Gain of disorder (P = 0.1116);.;.;.;.;.;.;
MVP		0.64
MPC		0.16
ClinPred		0.0065	T
GERP RS		2.2
Varity_R		0.072
gMVP		0.36

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: rs150724610; hg19: chr2-71753416;