2-219425981-A-G

Variant names:

• chr2-219425981-A-G
• rs397516691
• NM_001927.4:c.1404A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001927.4(DES):​c.1404A>G​(p.Glu468Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.218
• Publications: 0 publications found

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]

DES Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1I

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 1

  Inheritance: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• atrioventricular block

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurogenic scapuloperoneal syndrome, Kaeser type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000234638 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-219425981-A-G is Benign according to our data. Variant chr2-219425981-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44253.
• BP7: Synonymous conserved (PhyloP=0.218 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000226 (33/1461810) while in subpopulation AMR AF = 0.000738 (33/44724). AF 95% confidence interval is 0.000539. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.1404A>G	p.Glu468Glu	synonymous	Exon 9 of 9	NP_001918.3
	DES	NM_001382708.1		c.1401A>G	p.Glu467Glu	synonymous	Exon 9 of 9	NP_001369637.1
	DES	NM_001382711.1		c.1383A>G	p.Glu461Glu	synonymous	Exon 9 of 9	NP_001369640.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.1404A>G	p.Glu468Glu	synonymous	Exon 9 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.1527A>G	p.Glu509Glu	synonymous	Exon 10 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.1518A>G	p.Glu506Glu	synonymous	Exon 9 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251106 AF XY: 0.0000884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Desmin-related myofibrillar myopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.4
DANN	Benign	0.78
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs397516691; hg19: chr2-220290703;