2-219418870-C-T

Variant names:

• chr2-219418870-C-T
• rs111828114
• NM_001927.4:c.408C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001927.4(DES):​c.408C>T​(p.Leu136Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,573,926 control chromosomes in the GnomAD database, including 938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L136L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (76 hom., cov: 33)
  • Exomes 𝑓: 0.032 (862 hom.)
• Consequence: DES NM_001927.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.728
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-219418870-C-T is Benign according to our data. Variant chr2-219418870-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.728 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.026 (3956/152292) while in subpopulation NFE AF = 0.0389 (2642/67998). AF 95% confidence interval is 0.0376. There are 76 homozygotes in GnomAd4. There are 1911 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 SD,AR,AD gene

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.408C>T	p.Leu136Leu	synonymous	Exon 1 of 9	NP_001918.3
	DES	NM_001382708.1		c.408C>T	p.Leu136Leu	synonymous	Exon 1 of 9	NP_001369637.1
	DES	NM_001382712.1		c.408C>T	p.Leu136Leu	synonymous	Exon 1 of 9	NP_001369641.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.408C>T	p.Leu136Leu	synonymous	Exon 1 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.408C>T	p.Leu136Leu	synonymous	Exon 1 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.408C>T	p.Leu136Leu	synonymous	Exon 1 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3958 AN: 152176 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0266 AC: 4829 AN: 181540 AF XY: 0.0262

Gnomad AFR exome AF: 0.00558

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0320 AC: 45538 AN: 1421634 Hom.: 862 Cov.: 92 AF XY: 0.0314 AC XY: 22113 AN XY: 703480

African (AFR) AF: 0.00511 AC: 167 AN: 32672

American (AMR) AF: 0.0207 AC: 790 AN: 38166

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 885 AN: 25496

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37552

South Asian (SAS) AF: 0.00483 AC: 392 AN: 81196

European-Finnish (FIN) AF: 0.0452 AC: 2247 AN: 49732

Middle Eastern (MID) AF: 0.0327 AC: 186 AN: 5696

European-Non Finnish (NFE) AF: 0.0359 AC: 39203 AN: 1092192

Other (OTH) AF: 0.0283 AC: 1667 AN: 58932

GnomAD4 genome AF: 0.0260 AC: 3956 AN: 152292 Hom.: 76 Cov.: 33 AF XY: 0.0257 AC XY: 1911 AN XY: 74456

African (AFR) AF: 0.00611 AC: 254 AN: 41574

American (AMR) AF: 0.0231 AC: 354 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.0449 AC: 477 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0389 AC: 2642 AN: 67998

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0337 Hom.: 45

Bravo AF: 0.0239

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	not provided (3)
-	-	2	Desmin-related myofibrillar myopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1I (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)
-	-	1	Neurogenic scapuloperoneal syndrome, Kaeser type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		0.73
PromoterAI		-0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111828114; hg19: chr2-220283592; COSMIC: COSV64660176; COSMIC: COSV64660176;