rs1060502638
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_004006.3(DMD):c.2110C>T(p.Pro704Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000827 in 1,208,939 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )
Consequence
DMD
NM_004006.3 missense
NM_004006.3 missense
Scores
3
13
Clinical Significance
Conservation
PhyloP100: 4.02
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.17343059).
BS2
High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.2110C>T | p.Pro704Ser | missense_variant | 17/79 | ENST00000357033.9 | NP_003997.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.2110C>T | p.Pro704Ser | missense_variant | 17/79 | 1 | NM_004006.3 | ENSP00000354923.3 |
Frequencies
GnomAD3 genomes AF: 0.0000448 AC: 5AN: 111691Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2AN XY: 33889
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GnomAD3 exomes AF: 0.00000546 AC: 1AN: 183059Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67629
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GnomAD4 exome AF: 0.00000456 AC: 5AN: 1097248Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1AN XY: 362774
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GnomAD4 genome AF: 0.0000448 AC: 5AN: 111691Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2AN XY: 33889
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 11, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2021 | The p.P704S variant (also known as c.2110C>T), located in coding exon 17 of the DMD gene, results from a C to T substitution at nucleotide position 2110. The proline at codon 704 is replaced by serine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/204912) total alleles studied, with no hemizygotes observed. The highest observed frequency was 0.01% (2/19011) of African/African American alleles. This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Duchenne muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 704 of the DMD protein (p.Pro704Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 409910). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;N;D
REVEL
Benign
Sift
Benign
.;T;.;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
0.0060, 0.0030
.;B;.;.;B
Vest4
MutPred
0.29
.;.;Loss of catalytic residue at P704 (P = 0.0029);Loss of catalytic residue at P704 (P = 0.0029);.;
MVP
MPC
0.018
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at