rs36122356

Variant names:

• chr2-71520793-C-T
• rs36122356
• NM_001130987.2:c.1038C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-71520793-C-T
• chr2-71520793-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130987.2(DYSF):​c.1038C>T​(p.His346His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,613,280 control chromosomes in the GnomAD database, including 2,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (395 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2562 hom.)
• Consequence: DYSF NM_001130987.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.59
• 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=-0.69).
• BP6: Variant 2-71520793-C-T is Benign according to our data. Variant chr2-71520793-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0936 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.1038C>T	p.His346His	synonymous	Exon 12 of 56	NP_001124459.1	O75923-13
	DYSF	NM_003494.4	MANE Plus Clinical	c.942C>T	p.His314His	synonymous	Exon 11 of 55	NP_003485.1	O75923-1
	DYSF	NM_001130981.2		c.1035C>T	p.His345His	synonymous	Exon 12 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.1038C>T	p.His346His	synonymous	Exon 12 of 56	ENSP00000386881.3	O75923-13
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.942C>T	p.His314His	synonymous	Exon 11 of 55	ENSP00000258104.3	O75923-1
	DYSF	ENST00000409582.7	TSL:1	c.1035C>T	p.His345His	synonymous	Exon 12 of 56	ENSP00000386547.3	O75923-7

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9863 AN: 152022 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0961

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0578

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0540

Gnomad OTH AF: 0.0608

GnomAD2 exomes AF: 0.0565 AC: 14197 AN: 251450 AF XY: 0.0580

Gnomad AFR exome AF: 0.0972

Gnomad AMR exome AF: 0.0288

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.0504

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0647

GnomAD4 exome AF: 0.0560 AC: 81883 AN: 1461140 Hom.: 2562 Cov.: 32 AF XY: 0.0569 AC XY: 41336 AN XY: 726890

African (AFR) AF: 0.0992 AC: 3319 AN: 33454

American (AMR) AF: 0.0309 AC: 1384 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0989 AC: 2582 AN: 26120

East Asian (EAS) AF: 0.0691 AC: 2741 AN: 39686

South Asian (SAS) AF: 0.0802 AC: 6918 AN: 86228

European-Finnish (FIN) AF: 0.0285 AC: 1523 AN: 53408

Middle Eastern (MID) AF: 0.0941 AC: 538 AN: 5720

European-Non Finnish (NFE) AF: 0.0532 AC: 59150 AN: 1111444

Other (OTH) AF: 0.0618 AC: 3728 AN: 60360

GnomAD4 genome AF: 0.0649 AC: 9869 AN: 152140 Hom.: 395 Cov.: 32 AF XY: 0.0637 AC XY: 4739 AN XY: 74390

African (AFR) AF: 0.0961 AC: 3987 AN: 41476

American (AMR) AF: 0.0480 AC: 735 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3470

East Asian (EAS) AF: 0.0575 AC: 297 AN: 5162

South Asian (SAS) AF: 0.0800 AC: 385 AN: 4810

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0540 AC: 3671 AN: 68004

Other (OTH) AF: 0.0616 AC: 130 AN: 2112

Alfa AF: 0.0592 Hom.: 234

Bravo AF: 0.0654

Asia WGS AF: 0.0870 AC: 302 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0595

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	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 muscular dystrophy 1 (1)
-	-	1	Miyoshi myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.32
DANN	Benign	0.41
PhyloP100		-3.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs36122356; hg19: chr2-71747923; COSMIC: COSV50334856;