rs953271494

Positions:

• chrX-31496917-C-G
• chrX-31496917-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004006.3(DMD):​c.8418G>C​(p.Gln2806His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,652 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13846743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.8418G>C	p.Gln2806His	missense_variant	57/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.8418G>C	p.Gln2806His	missense_variant	57/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000113 AC: 2 AN: 176540 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 61532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000743

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000183 AC: 2 AN: 1095652 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000572

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	.;T;T;T;.;.;T;.;.;T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.77	T;.;.;.;.;T;.;T;T;.
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.19	N;.;N;N;N;.;N;.;N;N
REVEL	Benign	0.065
Sift	Benign	0.87	T;.;T;T;T;.;T;.;T;T
Sift4G	Benign	0.79	T;T;T;T;T;T;T;T;T;T
Polyphen		0.010, 0.028, 0.0, 0.0020	.;.;B;B;B;.;B;.;.;B
Vest4		0.34, 0.34, 0.31, 0.33, 0.30, 0.33, 0.32, 0.38, 0.33
MutPred		0.34		.;.;.;.;.;.;.;.;Loss of ubiquitination at K2808 (P = 0.0755);.;
MVP		0.71
MPC		0.034
ClinPred		0.41	T
GERP RS		5.0
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs953271494; hg19: chrX-31515034;