2-71513802-G-T

Variant names:

• chr2-71513802-G-T
• rs759455142
• NM_001130987.2:c.640G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001130987.2(DYSF):​c.640G>T​(p.Ala214Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.982

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain C2 2 (size 118) in uniprot entity DYSF_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09709406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.640G>T	p.Ala214Ser	missense_variant	Exon 7 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.544G>T	p.Ala182Ser	missense_variant	Exon 6 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.640G>T	p.Ala214Ser	missense_variant	Exon 7 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.544G>T	p.Ala182Ser	missense_variant	Exon 6 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251244 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Qualitative or quantitative defects of dysferlin Uncertain:1

Apr 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DYSF-related disease. This variant is present in population databases (rs759455142, ExAC 0.02%). This sequence change replaces alanine with serine at codon 182 of the DYSF protein (p.Ala182Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.097	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.46	.;.;N;.;N;.;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.45	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;P;B;B;B;B;B;B;B;B
Vest4		0.096
MutPred		0.21		.;.;Gain of glycosylation at A182 (P = 0.0074);.;Gain of glycosylation at A182 (P = 0.0074);.;.;.;.;.;.;
MVP		0.67
MPC		0.13
ClinPred		0.092	T
GERP RS		3.9
Varity_R		0.038
gMVP		0.18

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: rs759455142; hg19: chr2-71740932;