2-71556087-C-T

Position:

• chr2-71556087-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000410020.8(DYSF):​c.2216+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,548,608 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (9 hom., cov: 33)
  • Exomes 𝑓: 0.014 (177 hom.)
• Consequence: DYSF ENST00000410020.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.124

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-71556087-C-T is Benign according to our data. Variant chr2-71556087-C-T is described in ClinVar as [Benign]. Clinvar id is 94284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71556087-C-T is described in Lovd as [Likely_benign]. Variant chr2-71556087-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0138 (19266/1396300) while in subpopulation MID AF= 0.019 (79/4158). AF 95% confidence interval is 0.018. There are 177 homozygotes in gnomad4_exome. There are 9657 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.2216+16C>T		intron_variant		ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.2162+16C>T		intron_variant		ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000258104.8	c.2162+16C>T		intron_variant		1	NM_003494.4	ENSP00000258104	A1
DYSF	ENST00000410020.8	c.2216+16C>T		intron_variant		1	NM_001130987.2	ENSP00000386881	A1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1668 AN: 152190 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0130 AC: 2055 AN: 158676 Hom.: 22 AF XY: 0.0137 AC XY: 1150 AN XY: 84238

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.00835

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.00426

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0138 AC: 19266 AN: 1396300 Hom.: 177 Cov.: 30 AF XY: 0.0140 AC XY: 9657 AN XY: 689506

Gnomad4 AFR exome AF: 0.00271

Gnomad4 AMR exome AF: 0.00907

Gnomad4 ASJ exome AF: 0.0281

Gnomad4 EAS exome AF: 0.00168

Gnomad4 SAS exome AF: 0.0188

Gnomad4 FIN exome AF: 0.00374

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0110 AC: 1670 AN: 152308 Hom.: 9 Cov.: 33 AF XY: 0.0102 AC XY: 763 AN XY: 74482

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0276

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0128 Hom.: 1

Bravo AF: 0.0108

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Qualitative or quantitative defects of dysferlin Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.87

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: rs111389127; hg19: chr2-71783217;