2-71664231-C-T

Variant names:

• chr2-71664231-C-T
• rs2303599
• NM_001130987.2:c.5004-37C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.5004-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,612,854 control chromosomes in the GnomAD database, including 582,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48994 hom., cov: 31)
  • Exomes 𝑓: 0.85 (533871 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.734

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-71664231-C-T is Benign according to our data. Variant chr2-71664231-C-T is described in ClinVar as [Benign]. Clinvar id is 259081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71664231-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5004-37C>T		intron_variant	Intron 45 of 55	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4887-37C>T		intron_variant	Intron 44 of 54	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5004-37C>T		intron_variant	Intron 45 of 55	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4887-37C>T		intron_variant	Intron 44 of 54	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121260 AN: 151970 Hom.: 49008 Cov.: 31

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.804

GnomAD3 exomes AF: 0.816 AC: 205013 AN: 251146 Hom.: 84513 AF XY: 0.826 AC XY: 112223 AN XY: 135784

Gnomad AFR exome AF: 0.689

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.868

Gnomad EAS exome AF: 0.703

Gnomad SAS exome AF: 0.835

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.871

Gnomad OTH exome AF: 0.828

GnomAD4 exome AF: 0.853 AC: 1246058 AN: 1460766 Hom.: 533871 Cov.: 46 AF XY: 0.854 AC XY: 620576 AN XY: 726728

Gnomad4 AFR exome AF: 0.685

Gnomad4 AMR exome AF: 0.702

Gnomad4 ASJ exome AF: 0.864

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.838

Gnomad4 FIN exome AF: 0.853

Gnomad4 NFE exome AF: 0.873

Gnomad4 OTH exome AF: 0.837

GnomAD4 genome AF: 0.797 AC: 121280 AN: 152088 Hom.: 48994 Cov.: 31 AF XY: 0.795 AC XY: 59127 AN XY: 74328

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.853

Gnomad4 EAS AF: 0.685

Gnomad4 SAS AF: 0.818

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.866

Gnomad4 OTH AF: 0.796

Alfa AF: 0.846 Hom.: 56771

Bravo AF: 0.784

Asia WGS AF: 0.730 AC: 2540 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Distal myopathy with anterior tibial onset Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.030
DANN	Benign	0.44

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: rs2303599; hg19: chr2-71891361;