2-71516146-C-T

Variant names:

• chr2-71516146-C-T
• rs115184725
• NM_001130987.2:c.889-34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130987.2(DYSF):​c.889-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,603,320 control chromosomes in the GnomAD database, including 556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 33)
  • Exomes 𝑓: 0.024 (507 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.57
• Publications: 1 publications found

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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-71516146-C-T is Benign according to our data. Variant chr2-71516146-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2833/152348) while in subpopulation NFE AF = 0.0277 (1886/68036). AF 95% confidence interval is 0.0267. There are 49 homozygotes in GnomAd4. There are 1337 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.889-34C>T		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.793-34C>T		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.886-34C>T		intron	N/A	NP_001124453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.889-34C>T		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.793-34C>T		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.886-34C>T		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2833 AN: 152230 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0200 AC: 5030 AN: 251322 AF XY: 0.0206

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0243 AC: 35295 AN: 1450972 Hom.: 507 Cov.: 30 AF XY: 0.0241 AC XY: 17377 AN XY: 722466

African (AFR) AF: 0.00390 AC: 130 AN: 33294

American (AMR) AF: 0.0135 AC: 602 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 1532 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00889 AC: 765 AN: 86060

European-Finnish (FIN) AF: 0.0155 AC: 828 AN: 53414

Middle Eastern (MID) AF: 0.0289 AC: 166 AN: 5744

European-Non Finnish (NFE) AF: 0.0271 AC: 29843 AN: 1102034

Other (OTH) AF: 0.0238 AC: 1429 AN: 60002

GnomAD4 genome AF: 0.0186 AC: 2833 AN: 152348 Hom.: 49 Cov.: 33 AF XY: 0.0179 AC XY: 1337 AN XY: 74494

African (AFR) AF: 0.00459 AC: 191 AN: 41584

American (AMR) AF: 0.0203 AC: 311 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4826

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0277 AC: 1886 AN: 68036

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0275 Hom.: 13

Bravo AF: 0.0182

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Miyoshi muscular dystrophy 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.64
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs115184725; hg19: chr2-71743276;