NM_001130987.2:c.1145C>T

Variant names:

• chr2-71520900-C-T
• rs115279465
• NM_001130987.2:c.1145C>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.1145C>T​(p.Ala382Val) variant causes a missense change. The variant allele was found at a frequency of 0.000709 in 1,613,988 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. A382A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (6 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.89
• 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011333644).
• BP6: Variant 2-71520900-C-T is Benign according to our data. Variant chr2-71520900-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00328 (499/152254) while in subpopulation AFR AF = 0.0111 (460/41536). AF 95% confidence interval is 0.0102. There are 0 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1145C>T	p.Ala382Val	missense	Exon 12 of 56	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.1049C>T	p.Ala350Val	missense	Exon 11 of 55	NP_003485.1
	DYSF	NM_001130981.2		c.1142C>T	p.Ala381Val	missense	Exon 12 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.1145C>T	p.Ala382Val	missense	Exon 12 of 56	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.1049C>T	p.Ala350Val	missense	Exon 11 of 55	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.1142C>T	p.Ala381Val	missense	Exon 12 of 56	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000899 AC: 226 AN: 251426 AF XY: 0.000795

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000441 AC: 645 AN: 1461734 Hom.: 6 Cov.: 32 AF XY: 0.000396 AC XY: 288 AN XY: 727168

African (AFR) AF: 0.0127 AC: 426 AN: 33478

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00252 AC: 100 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5736

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111916

Other (OTH) AF: 0.000679 AC: 41 AN: 60388

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74444

African (AFR) AF: 0.0111 AC: 460 AN: 41536

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00163 Hom.: 1

Bravo AF: 0.00363

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00119 AC: 145

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2B (1)
-	-	1	DYSF-related disorder (1)
-	-	1	Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.093
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.019	D
Sift4G	Benign	0.28	T
Polyphen		0.42	B
Vest4		0.45
MVP		0.80
MPC		0.35
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.073
gMVP		0.32
Mutation Taster		=98/2	polymorphism

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: rs115279465; hg19: chr2-71748030;