rs6546693

Variant names:

• chr2-71453502-T-C
• rs6546693
• ENST00000685766.2:n.969A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000685766.2(ENSG00000289327):​n.969A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,110 control chromosomes in the GnomAD database, including 2,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.16 (2867 hom., cov: 32)
• Consequence: ENSG00000289327 ENST00000685766.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.118
• Publications: 5 publications found

Genes affected

ENSG00000289327 (HGNC:):

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]

DYSF Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-71453502-T-C is Benign according to our data. Variant chr2-71453502-T-C is described in ClinVar as Benign. ClinVar VariationId is 679856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000685766.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_003494.4	MANE Plus Clinical	c.-497T>C		upstream_gene	N/A	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.-497T>C		upstream_gene	N/A	NP_001124453.1	O75923-7
	DYSF	NM_001130979.2		c.-497T>C		upstream_gene	N/A	NP_001124451.1	O75923-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000289327	ENST00000685766.2		n.969A>G		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000289327	ENST00000732375.1		n.846A>G		non_coding_transcript_exon	Exon 2 of 2
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.-497T>C		upstream_gene	N/A	ENSP00000258104.3	O75923-1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24166 AN: 151992 Hom.: 2864 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0767

Gnomad OTH AF: 0.147

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.159 AC: 24196 AN: 152110 Hom.: 2867 Cov.: 32 AF XY: 0.163 AC XY: 12085 AN XY: 74368

African (AFR) AF: 0.286 AC: 11858 AN: 41482

American (AMR) AF: 0.115 AC: 1757 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3472

East Asian (EAS) AF: 0.496 AC: 2554 AN: 5146

South Asian (SAS) AF: 0.154 AC: 744 AN: 4824

European-Finnish (FIN) AF: 0.109 AC: 1151 AN: 10586

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0767 AC: 5216 AN: 67994

Other (OTH) AF: 0.144 AC: 303 AN: 2110

Alfa AF: 0.113 Hom.: 3593

Bravo AF: 0.170

Asia WGS AF: 0.314 AC: 1090 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.5
DANN	Benign	0.65
PhyloP100		-0.12
PromoterAI		0.020	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6546693; hg19: chr2-71680632;