2-71513823-C-G

Variant names:

• chr2-71513823-C-G
• rs13407355
• NM_001130987.2:c.661C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130987.2(DYSF):​c.661C>G​(p.Leu221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,614,184 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L221L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (105 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.34
• Publications: 12 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 (MetaRNN=0.001826644).
• BP6: Variant 2-71513823-C-G is Benign according to our data. Variant chr2-71513823-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0665 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.661C>G	p.Leu221Val	missense	Exon 7 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.565C>G	p.Leu189Val	missense	Exon 6 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.658C>G	p.Leu220Val	missense	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.661C>G	p.Leu221Val	missense	Exon 7 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.565C>G	p.Leu189Val	missense	Exon 6 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.658C>G	p.Leu220Val	missense	Exon 7 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3164 AN: 152186 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0686

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00671 AC: 1686 AN: 251414 AF XY: 0.00512

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0202

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00274 AC: 4011 AN: 1461880 Hom.: 105 Cov.: 32 AF XY: 0.00243 AC XY: 1770 AN XY: 727238

African (AFR) AF: 0.0720 AC: 2412 AN: 33480

American (AMR) AF: 0.00438 AC: 196 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0193 AC: 768 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.000147 AC: 164 AN: 1112002

Other (OTH) AF: 0.00672 AC: 406 AN: 60394

GnomAD4 genome AF: 0.0208 AC: 3169 AN: 152304 Hom.: 103 Cov.: 32 AF XY: 0.0204 AC XY: 1520 AN XY: 74478

African (AFR) AF: 0.0686 AC: 2850 AN: 41572

American (AMR) AF: 0.00901 AC: 138 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68010

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.00396 Hom.: 15

Bravo AF: 0.0238

ESP6500AA AF: 0.0667 AC: 294

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00778 AC: 945

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.18
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.67
MPC		0.15
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.063
gMVP		0.16
Mutation Taster		=98/2	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: rs13407355; hg19: chr2-71740953;