chr2-71513828-T-C

Variant names:

• chr2-71513828-T-C
• rs35392229
• NM_001130987.2:c.666T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130987.2(DYSF):​c.666T>C​(p.Pro222Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,128 control chromosomes in the GnomAD database, including 1,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (125 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1240 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.11
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-71513828-T-C is Benign according to our data. Variant chr2-71513828-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0315 (4793/152254) while in subpopulation NFE AF = 0.0404 (2748/68000). AF 95% confidence interval is 0.0392. There are 125 homozygotes in GnomAd4. There are 2552 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 125 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.666T>C	p.Pro222Pro	synonymous	Exon 7 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.570T>C	p.Pro190Pro	synonymous	Exon 6 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.663T>C	p.Pro221Pro	synonymous	Exon 7 of 56	NP_001124453.1	O75923-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.666T>C	p.Pro222Pro	synonymous	Exon 7 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.570T>C	p.Pro190Pro	synonymous	Exon 6 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.663T>C	p.Pro221Pro	synonymous	Exon 7 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4798 AN: 152136 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0332 AC: 8358 AN: 251416 AF XY: 0.0339

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0382 AC: 55854 AN: 1461874 Hom.: 1240 Cov.: 32 AF XY: 0.0375 AC XY: 27251 AN XY: 727238

African (AFR) AF: 0.00597 AC: 200 AN: 33480

American (AMR) AF: 0.0228 AC: 1018 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00918 AC: 240 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0131 AC: 1133 AN: 86256

European-Finnish (FIN) AF: 0.0882 AC: 4713 AN: 53420

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5768

European-Non Finnish (NFE) AF: 0.0419 AC: 46553 AN: 1111996

Other (OTH) AF: 0.0316 AC: 1911 AN: 60394

GnomAD4 genome AF: 0.0315 AC: 4793 AN: 152254 Hom.: 125 Cov.: 32 AF XY: 0.0343 AC XY: 2552 AN XY: 74456

African (AFR) AF: 0.00748 AC: 311 AN: 41564

American (AMR) AF: 0.0334 AC: 511 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4826

European-Finnish (FIN) AF: 0.0943 AC: 1000 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0404 AC: 2748 AN: 68000

Other (OTH) AF: 0.0364 AC: 77 AN: 2114

Alfa AF: 0.0352 Hom.: 41

Bravo AF: 0.0270

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0387

EpiControl AF: 0.0405

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.52
PhyloP100		1.1
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: rs35392229; hg19: chr2-71740958;