rs35984374

Variant names:

• chr2-71551699-G-A
• rs35984374
• NM_001130987.2:c.1785G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-71551699-G-A
• chr2-71551699-G-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.1785G>A​(p.Ala595Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,609,232 control chromosomes in the GnomAD database, including 376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.016 (31 hom., cov: 33)
  • Exomes 𝑓: 0.020 (345 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -7.16
• Publications: 3 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

Specifications for DYSF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-71551699-G-A is Benign according to our data. Variant chr2-71551699-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2435/152182) while in subpopulation NFE AF = 0.0254 (1727/67996). AF 95% confidence interval is 0.0244. There are 31 homozygotes in GnomAd4. There are 1208 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 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.1785G>A	p.Ala595Ala	synonymous	Exon 19 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.1731G>A	p.Ala577Ala	synonymous	Exon 19 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1782G>A	p.Ala594Ala	synonymous	Exon 19 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.1785G>A	p.Ala595Ala	synonymous	Exon 19 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1731G>A	p.Ala577Ala	synonymous	Exon 19 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1782G>A	p.Ala594Ala	synonymous	Exon 19 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2435 AN: 152064 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00983

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0154 AC: 3707 AN: 240612 AF XY: 0.0153

Gnomad AFR exome AF: 0.00335

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.00787

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0198 AC: 28848 AN: 1457050 Hom.: 345 Cov.: 31 AF XY: 0.0192 AC XY: 13923 AN XY: 724054

African (AFR) AF: 0.00290 AC: 97 AN: 33472

American (AMR) AF: 0.00674 AC: 297 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00747 AC: 193 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.000177 AC: 15 AN: 84812

European-Finnish (FIN) AF: 0.0283 AC: 1485 AN: 52466

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.0232 AC: 25813 AN: 1110830

Other (OTH) AF: 0.0156 AC: 942 AN: 60256

GnomAD4 genome AF: 0.0160 AC: 2435 AN: 152182 Hom.: 31 Cov.: 33 AF XY: 0.0162 AC XY: 1208 AN XY: 74394

African (AFR) AF: 0.00402 AC: 167 AN: 41524

American (AMR) AF: 0.00981 AC: 150 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.0320 AC: 340 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1727 AN: 67996

Other (OTH) AF: 0.0124 AC: 26 AN: 2104

Alfa AF: 0.0205 Hom.: 31

Bravo AF: 0.0131

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.36
PhyloP100		-7.2
Mutation Taster		=87/13	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: rs35984374; hg19: chr2-71778829; COSMIC: COSV50287131;