rs578191306

chr2-219420854-C-Achr2-219420854-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001927.4(DES):c.924C>A(p.Asn308Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N308N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.475

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Interaction with NEB (size 147) in uniprot entity DESM_HUMAN there are 85 pathogenic changes around while only 6 benign (93%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30800477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.924C>A	p.Asn308Lys	missense_variant	5/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.924C>A	p.Asn308Lys	missense_variant	5/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.398C>A		non_coding_transcript_exon_variant	4/8	4
DES	ENST00000492726.1	n.319C>A		non_coding_transcript_exon_variant	4/6	4
DES	ENST00000683013.1	n.312C>A		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461606 Hom.: 0 Cov.: 38 AF XY: 0.00000413 AC XY: 3 AN XY: 727116

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
CardioboostCm	Benign	0.016
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.31	N
MutationTaster	Benign	0.66	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.32	T
Sift4G	Benign	0.93	T
Polyphen		0.0080	B
Vest4		0.56
MutPred		0.45		Loss of ubiquitination at K309 (P = 0.0236);
MVP		0.76
MPC		0.65
ClinPred		0.097	T
GERP RS		2.1
Varity_R		0.22
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs578191306; hg19: chr2-220285576;