X-31968489-C-T

Variant names:

• chrX-31968489-C-T
• rs892121336
• NM_004006.3:c.6464G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_004006.3(DMD):​c.6464G>A​(p.Arg2155Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000082 in 1,097,057 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. R2155W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000082 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.18
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10236034).
• BP6: Variant X-31968489-C-T is Benign according to our data. Variant chrX-31968489-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582667.
• BS2: High AC in GnomAdExome4 at 9 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.6464G>A	p.Arg2155Gln	missense	Exon 45 of 79	NP_003997.2
	DMD	NM_004009.3		c.6452G>A	p.Arg2151Gln	missense	Exon 45 of 79	NP_004000.1
	DMD	NM_000109.4		c.6440G>A	p.Arg2147Gln	missense	Exon 45 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.6464G>A	p.Arg2155Gln	missense	Exon 45 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.6452G>A	p.Arg2151Gln	missense	Exon 45 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.2432G>A	p.Arg811Gln	missense	Exon 17 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182317 AF XY: 0.0000149

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097057 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363019

African (AFR) AF: 0.0000760 AC: 2 AN: 26329

American (AMR) AF: 0.0000570 AC: 2 AN: 35078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19331

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40485

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841393

Other (OTH) AF: 0.00 AC: 0 AN: 46016

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Dec 02, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1

May 12, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Duchenne muscular dystrophy Benign:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.13
Sift	Benign	0.97	T
Sift4G	Benign	0.75	T
Polyphen		0.015	B
Vest4		0.23
MutPred		0.62		Loss of catalytic residue at R2155 (P = 0.0452)
MVP		0.39
MPC		0.038
ClinPred		0.064	T
GERP RS		4.4
gMVP		0.038
Mutation Taster		=96/4	polymorphism

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: rs892121336; hg19: chrX-31986606;