2-71611527-C-T

Variant names:

• chr2-71611527-C-T
• rs2303607
• NM_001130987.2:c.4122C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):​c.4122C>T​(p.Ser1374Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,170 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 33)
  • Exomes 𝑓: 0.027 (714 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.42
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-71611527-C-T is Benign according to our data. Variant chr2-71611527-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.42 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.4122C>T	p.Ser1374Ser	synonymous	Exon 38 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.4068C>T	p.Ser1356Ser	synonymous	Exon 38 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.4119C>T	p.Ser1373Ser	synonymous	Exon 38 of 56	NP_001124453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.4122C>T	p.Ser1374Ser	synonymous	Exon 38 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4068C>T	p.Ser1356Ser	synonymous	Exon 38 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.4119C>T	p.Ser1373Ser	synonymous	Exon 38 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3370 AN: 152182 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0319 AC: 8015 AN: 251364 AF XY: 0.0319

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0586

Gnomad ASJ exome AF: 0.0682

Gnomad EAS exome AF: 0.0364

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0272 AC: 39810 AN: 1461870 Hom.: 714 Cov.: 35 AF XY: 0.0275 AC XY: 19991 AN XY: 727240

African (AFR) AF: 0.00579 AC: 194 AN: 33480

American (AMR) AF: 0.0561 AC: 2510 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1829 AN: 26136

East Asian (EAS) AF: 0.0472 AC: 1873 AN: 39700

South Asian (SAS) AF: 0.0434 AC: 3744 AN: 86256

European-Finnish (FIN) AF: 0.0158 AC: 846 AN: 53406

Middle Eastern (MID) AF: 0.0326 AC: 188 AN: 5768

European-Non Finnish (NFE) AF: 0.0241 AC: 26845 AN: 1112008

Other (OTH) AF: 0.0295 AC: 1781 AN: 60394

GnomAD4 genome AF: 0.0221 AC: 3370 AN: 152300 Hom.: 62 Cov.: 33 AF XY: 0.0224 AC XY: 1665 AN XY: 74458

African (AFR) AF: 0.00623 AC: 259 AN: 41580

American (AMR) AF: 0.0415 AC: 636 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3472

East Asian (EAS) AF: 0.0377 AC: 195 AN: 5168

South Asian (SAS) AF: 0.0443 AC: 213 AN: 4812

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10622

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0234 AC: 1593 AN: 68020

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0216 Hom.: 32

Bravo AF: 0.0245

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.0255

EpiControl AF: 0.0250

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi muscular dystrophy 1 (1)
-	-	1	Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.5
DANN	Benign	0.68
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2303607; hg19: chr2-71838657;