rs145007061

chr2-71556002-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130987.2(DYSF):c.2147C>T(p.Ala716Val) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,574,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A716A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.19

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016065598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.2147C>T	p.Ala716Val	missense_variant	22/56	ENST00000410020.8
DYSF	NM_003494.4	c.2093C>T	p.Ala698Val	missense_variant	22/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.2147C>T	p.Ala716Val	missense_variant	22/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.2093C>T	p.Ala698Val	missense_variant	22/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000181 AC: 34 AN: 187634 Hom.: 0 AF XY: 0.000140 AC XY: 14 AN XY: 99922

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000819

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000858 AC: 122 AN: 1421674 Hom.: 0 Cov.: 32 AF XY: 0.0000882 AC XY: 62 AN XY: 703116

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000229

Gnomad4 OTH exome AF: 0.0000848

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74474

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000888

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000194 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 23, 2020

- -

Qualitative or quantitative defects of dysferlin Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.020	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.094	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.34
MVP		0.83
MPC		0.17
ClinPred		0.069	T
GERP RS		3.3
Varity_R		0.24
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145007061; hg19: chr2-71783132;