chr2-71551601-T-A

Position:

chr2-71551601-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001130987.2(DYSF):c.1693-6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,600,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.268

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-71551601-T-A is Pathogenic according to our data. Variant chr2-71551601-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 265488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71551601-T-A is described in Lovd as [Pathogenic]. Variant chr2-71551601-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.1693-6T>A		splice_region_variant, intron_variant		ENST00000410020.8	NP_001124459.1	O75923-13
DYSF	NM_003494.4 linkuse as main transcript	c.1639-6T>A		splice_region_variant, intron_variant		ENST00000258104.8	NP_003485.1	O75923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.1693-6T>A		splice_region_variant, intron_variant		1	NM_001130987.2	ENSP00000386881.3		O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.1639-6T>A		splice_region_variant, intron_variant		1	NM_003494.4	ENSP00000258104.3		O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000437

AC:

AN:

228892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000552

AC:

AN:

1448530

Hom.:

Cov.:

AF XY:

0.00000695

AC XY:

AN XY:

719014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000722

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2017	The c.1639-6T>A pathogenic variant in the DYSF gene has been reported previously in association with DYSF-related disorders when present in the homozygous state or when seen with another variant (Kesper et al., 2009; Ankala et al., 2014; Cacciottolo et al., 2011). Functional studies demonstrate the use of a cryptic acceptor site of intron 19 that results in the retention of 4 base pairs of intronic DNA, which is predicted to result in a truncated protein (Cacciottolo et al., 2011; Kergourlay et al., 2014). The c.1639-6T>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1639-6T>A as a pathogenic variant. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 01, 2020	- -

Qualitative or quantitative defects of dysferlin

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Jain Foundation	Mar 13, 2023	This variant has been observed in individuals with clinical features of dysferlinopathy in both the homozygous state (PMID: 21522182) and in the heterzygous state in conjunction with another pathogenic DYSF variant c.5503A>G (PMID:30564623, 36983702). It has also been identified in one family with dysferlinopathy, segregating with the disease in 2 affected siblings, and was associated with absent dysferlin protein expression (PMID:36983702). RNAseq showed that the c.1639-6T>A variant leads to the use of a cryptic splice acceptor site in intron 18 that results in the retention of 4 bps of intronic DNA in exon 19 after splicing which leads to a frameshift (p.Gly547AlafsX24; PMID:36983702). The ACMG classification criteria are: PM2 moderate, PM3 moderate, PP1 supporting, PP4 moderate, and PS3 strong. Based on the above data, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in insertion of 4 nucleotides from intron 18 and introduces a premature termination codon (PMID: 21522182, 25312915). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 265488). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 19154541, 21522182, 24488599, 30919934). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 18 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

Miyoshi muscular dystrophy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 2

DS_AL_spliceai

0.40

Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over