chrX-32362788-CT-AC

Variant names:

• chrX-32362788-CT-AC
• rs1557303381
• NM_004006.3:c.5324_5325delAGinsGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004006.3(DMD):​c.5324_5325delAGinsGT​(p.Lys1775Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000341 in 7 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1775N) has been classified as Uncertain significance.

• Frequency: GnomAD MNV: 𝑓 0.000034 Genomes: not found (cov: 22)
• Consequence: DMD NM_004006.3 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:1
• Conservation: PhyloP100: 6.87
• Publications: 0 publications found

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]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant X-32362788-CT-AC is Benign according to our data. Variant chrX-32362788-CT-AC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 492824.
• BS2: High AC in GnomAdMnv at 7 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. 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
	DMD	NM_004006.3	MANE Select	c.5324_5325delAGinsGT	p.Lys1775Ser	missense splice_region	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5312_5313delAGinsGT	p.Lys1771Ser	missense splice_region	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.5300_5301delAGinsGT	p.Lys1767Ser	missense splice_region	N/A	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.5324_5325delAGinsGT	p.Lys1775Ser	missense splice_region	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5312_5313delAGinsGT	p.Lys1771Ser	missense splice_region	N/A	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1292_1293delAGinsGT	p.Lys431Ser	missense splice_region	N/A	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

GnomAD MNV AF: 0.0000341 AC: 7 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	Duchenne muscular dystrophy (2)
1	-	-	Becker muscular dystrophy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9

Splicing

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

Other links and lift over

dbSNP: rs1557303381; hg19: chrX-32380905;