chrX-31496944-CC-TT

Variant names:

• chrX-31496944-CC-TT
• rs1060502619
• NM_004006.3:c.8391-1_8391delGGinsAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004006.3(DMD):​c.8391-1_8391delGGinsAA​(p.2798) variant causes a splice acceptor, splice region, synonymous, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: DMD NM_004006.3 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.38

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of -35, new splice context is: atcatcaattacacttctAGata. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-31496944-CC-TT is Pathogenic according to our data. Variant chrX-31496944-CC-TT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.8391-1_8391delGGinsAA	p.2798	splice_acceptor_variant, splice_region_variant, synonymous_variant, intron_variant		ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.8391-1_8391delGGinsAA	p.2798	splice_acceptor_variant, splice_region_variant, synonymous_variant, intron_variant		1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Pathogenic:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Pathogenic:1

Jul 22, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Likely Pathogenic. This sequence change affects an acceptor splice site in intron 56 of the DMD gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This sequence change also effects the first nucleotide of exon 57. A similar variant, which is predicted to have the same effect on splicing (c.8391-1G>A) has been reported in the literature in an individual affected with Duchenne muscular dystrophy (DMD)  (PMID: 20485447). In addition, other splice site variants in DMD are known to be pathogenic (PMID: 16770791). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502619; hg19: chrX-31515061;