X-31875221-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004006.3(DMD):c.7065C>A(p.Asn2355Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,321 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2355S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.534

Publications

0 publications found

Variant links:

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

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15606579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.7065C>A	p.Asn2355Lys	missense_variant	Exon 48 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.7065C>A	p.Asn2355Lys	missense_variant	Exon 48 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000569

AC:

AN:

175718

AF XY:

0.0000164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1084321

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353869

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25943

American (AMR)

AF:

0.00

AC:

AN:

34567

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18788

East Asian (EAS)

AF:

0.00

AC:

AN:

29181

South Asian (SAS)

AF:

0.00

AC:

AN:

53124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4051

European-Non Finnish (NFE)

AF:

0.00000240

AC:

AN:

833488

Other (OTH)

AF:

0.00

AC:

AN:

45245

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 05, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 19, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Duchenne muscular dystrophy

Uncertain:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2355 of the DMD protein (p.Asn2355Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 284978). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

.;.;T;.;.

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.68

T;T;.;T;T

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.53

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.95

N;.;N;.;N

REVEL

Benign

0.011

Sift

Benign

0.043

D;.;T;.;T

Sift4G

Benign

0.86

T;T;T;T;T

Polyphen

0.15

.;.;B;.;.

Vest4

0.20, 0.14, 0.19, 0.14

MutPred

0.39

.;.;.;.;Gain of ubiquitination at N2355 (P = 0.0066);

MVP

0.55

MPC

0.016

ClinPred

0.13

GERP RS

0.37

PromoterAI

-0.011

Neutral

(source)

gMVP

0.067

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over