rs1157722667

Variant names:

• chr2-219420929-C-G
• NM_001927.4:c.999C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-219420929-C-G
• chr2-219420929-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001927.4(DES):​c.999C>G​(p.Cys333Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25

Genes affected

DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Interaction with NEB (size 147) in uniprot entity DESM_HUMAN there are 50 pathogenic changes around while only 2 benign (96%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.999C>G	p.Cys333Trp	missense_variant	Exon 5 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.999C>G	p.Cys333Trp	missense_variant	Exon 5 of 9	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.473C>G		non_coding_transcript_exon_variant	Exon 4 of 8	4
DES	ENST00000492726.1	n.394C>G		non_coding_transcript_exon_variant	Exon 4 of 6	4
DES	ENST00000683013.1	n.387C>G		non_coding_transcript_exon_variant	Exon 3 of 7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461240 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jul 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C333W variant (also known as c.999C>G), located in coding exon 5 of the DES gene, results from a C to G substitution at nucleotide position 999. The cysteine at codon 333 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.11
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.58		Gain of MoRF binding (P = 0.0311);
MVP		0.99
MPC		1.7
ClinPred		0.97	D
GERP RS		0.98
Varity_R		0.95
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220285651;