NM_001130987.2:c.4222-20G>A

Variant names:

• chr2-71612621-G-A
• rs111935215
• NM_001130987.2:c.4222-20G>A

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.4222-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,612,970 control chromosomes in the GnomAD database, including 642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 33)
  • Exomes 𝑓: 0.025 (586 hom.)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.696
• 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 (BayesDel_noAF=-0.89).
• BP6: Variant 2-71612621-G-A is Benign according to our data. Variant chr2-71612621-G-A is described in ClinVar as Benign. ClinVar VariationId is 94319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0247 (3757/152322) while in subpopulation SAS AF = 0.0425 (205/4828). AF 95% confidence interval is 0.0377. There are 56 homozygotes in GnomAd4. There are 1815 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	NM_001130987.2	MANE Select	c.4222-20G>A		intron	N/A	NP_001124459.1
	DYSF	NM_003494.4	MANE Plus Clinical	c.4168-20G>A		intron	N/A	NP_003485.1
	DYSF	NM_001130981.2		c.4219-20G>A		intron	N/A	NP_001124453.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYSF	ENST00000410020.8	TSL:1 MANE Select	c.4222-20G>A		intron	N/A	ENSP00000386881.3
	DYSF	ENST00000258104.8	TSL:1 MANE Plus Clinical	c.4168-20G>A		intron	N/A	ENSP00000258104.3
	DYSF	ENST00000409582.7	TSL:1	c.4219-20G>A		intron	N/A	ENSP00000386547.3

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3753 AN: 152204 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0662

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0236 AC: 5920 AN: 250586 AF XY: 0.0251

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0731

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0248 AC: 36185 AN: 1460648 Hom.: 586 Cov.: 31 AF XY: 0.0253 AC XY: 18354 AN XY: 726362

African (AFR) AF: 0.0310 AC: 1037 AN: 33456

American (AMR) AF: 0.0123 AC: 551 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 1964 AN: 26112

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39664

South Asian (SAS) AF: 0.0429 AC: 3698 AN: 86174

European-Finnish (FIN) AF: 0.0113 AC: 601 AN: 53368

Middle Eastern (MID) AF: 0.0344 AC: 198 AN: 5760

European-Non Finnish (NFE) AF: 0.0238 AC: 26460 AN: 1111102

Other (OTH) AF: 0.0277 AC: 1672 AN: 60334

GnomAD4 genome AF: 0.0247 AC: 3757 AN: 152322 Hom.: 56 Cov.: 33 AF XY: 0.0244 AC XY: 1815 AN XY: 74480

African (AFR) AF: 0.0296 AC: 1231 AN: 41574

American (AMR) AF: 0.0206 AC: 315 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 230 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4828

European-Finnish (FIN) AF: 0.00876 AC: 93 AN: 10622

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1550 AN: 68034

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0301 Hom.: 17

Bravo AF: 0.0249

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 04, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Miyoshi muscular dystrophy 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.12
DANN	Benign	0.49
PhyloP100		-0.70
Mutation Taster		=100/0	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: rs111935215; hg19: chr2-71839751; COSMIC: COSV50461912;