rs145401010

Variant names:

• chr2-71611314-A-G
• rs145401010
• NM_001130987.2:c.4027A>G
• DYSF p.Ile1343Val

Your query was ambiguous. Multiple possible variants found:

• chr2-71611314-A-G
• chr2-71611314-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001130987.2(DYSF):​c.4027A>G​(p.Ile1343Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,613,996 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene DYSF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (3 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 9.32
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008916825).
• BP6: Variant 2-71611314-A-G is Benign according to our data. Variant chr2-71611314-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 336969.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00392 (597/152300) while in subpopulation AFR AF = 0.014 (584/41568). AF 95% confidence interval is 0.0131. There are 1 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.4027A>G	p.Ile1343Val	missense	Exon 37 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.3973A>G	p.Ile1325Val	missense	Exon 37 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.4024A>G	p.Ile1342Val	missense	Exon 37 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.4027A>G	p.Ile1343Val	missense	Exon 37 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.3973A>G	p.Ile1325Val	missense	Exon 37 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.4024A>G	p.Ile1342Val	missense	Exon 37 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152182 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000905 AC: 227 AN: 250768 AF XY: 0.000583

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000436 AC: 637 AN: 1461696 Hom.: 3 Cov.: 33 AF XY: 0.000399 AC XY: 290 AN XY: 727126

African (AFR) AF: 0.0150 AC: 501 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111872

Other (OTH) AF: 0.000712 AC: 43 AN: 60374

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74482

African (AFR) AF: 0.0140 AC: 584 AN: 41568

American (AMR) AF: 0.000522 AC: 8 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00127 Hom.: 2

Bravo AF: 0.00441

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	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 myopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	-0.0061	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.037	D
Varity_R		0.13
gMVP		0.49
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145401010;

hg19: chr2-71838444;