rs1443021146

Variant names:

• chrX-32501838-A-G
• rs1443021146
• NM_004006.3:c.2297T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_004006.3(DMD):​c.2297T>C​(p.Ile766Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,083,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. I766V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.43
• 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

ENSG00000297605 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BP6: Variant X-32501838-A-G is Benign according to our data. Variant chrX-32501838-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455878.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.2297T>C	p.Ile766Thr	missense_variant	Exon 19 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.2297T>C	p.Ile766Thr	missense_variant	Exon 19 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000119 AC: 2 AN: 168258 AF XY: 0.0000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000379

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: 0.000235

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1083158 Hom.: 0 Cov.: 28 AF XY: 0.00000286 AC XY: 1 AN XY: 349600

African (AFR) AF: 0.00 AC: 0 AN: 26217

American (AMR) AF: 0.0000288 AC: 1 AN: 34677

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19200

East Asian (EAS) AF: 0.00 AC: 0 AN: 30106

South Asian (SAS) AF: 0.00 AC: 0 AN: 52498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40157

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 830599

Other (OTH) AF: 0.0000219 AC: 1 AN: 45598

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 22, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Feb 18, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I766T variant (also known as c.2297T>C), located in coding exon 19 of the DMD gene, results from a T to C substitution at nucleotide position 2297. The isoleucine at codon 766 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy Benign:1

Sep 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.65	T
PhyloP100		7.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	.;N;.;N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	.;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.72
MutPred		0.48		.;.;Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP		0.83
MPC		0.066
ClinPred		0.53	D
GERP RS		5.3
gMVP		0.31
Mutation Taster		=89/11	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: rs1443021146; hg19: chrX-32519955;