chr2-219420154-C-T

Variant names:

• chr2-219420154-C-T
• rs41272699
• NM_001927.4:c.638C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_001382708.1(DES):​c.636+2C>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,216 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0099 (12 hom., cov: 32)
  • Exomes 𝑓: 0.015 (221 hom.)
• Consequence: DES NM_001382708.1 splice_donor, intron
• Scores: Splicing: ADA: 0.05342
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:25 O:1
• Conservation: PhyloP100: 1.51
• Publications: 35 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 -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.041134752 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.9, offset of 3, new splice context is: gtgGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 2-219420154-C-T is Benign according to our data. Variant chr2-219420154-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44265.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00989 (1506/152346) while in subpopulation NFE AF = 0.0158 (1077/68030). AF 95% confidence interval is 0.015. There are 12 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 SD,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382708.1. 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.638C>T	p.Ala213Val	missense splice_region	Exon 2 of 9	NP_001918.3
	DES	NM_001382712.1		c.638C>T	p.Ala213Val	missense splice_region	Exon 2 of 9	NP_001369641.1
	DES	NM_001382711.1		c.638C>T	p.Ala213Val	missense splice_region	Exon 2 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.638C>T	p.Ala213Val	missense splice_region	Exon 2 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.638C>T	p.Ala213Val	missense splice_region	Exon 2 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.638C>T	p.Ala213Val	missense splice_region	Exon 2 of 9	ENSP00000612957.1

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1505 AN: 152228 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00921 AC: 2315 AN: 251474 AF XY: 0.00996

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00575

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00734

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.0146 AC: 21307 AN: 1461870 Hom.: 221 Cov.: 36 AF XY: 0.0142 AC XY: 10361 AN XY: 727236

African (AFR) AF: 0.00263 AC: 88 AN: 33480

American (AMR) AF: 0.00617 AC: 276 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00345 AC: 298 AN: 86258

European-Finnish (FIN) AF: 0.00889 AC: 475 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0174 AC: 19328 AN: 1111988

Other (OTH) AF: 0.0130 AC: 787 AN: 60396

GnomAD4 genome AF: 0.00989 AC: 1506 AN: 152346 Hom.: 12 Cov.: 32 AF XY: 0.00890 AC XY: 663 AN XY: 74492

African (AFR) AF: 0.00320 AC: 133 AN: 41582

American (AMR) AF: 0.00934 AC: 143 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1077 AN: 68030

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.0133 Hom.: 62

Bravo AF: 0.00963

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.0101 AC: 1232

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0149

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (6)
-	-	3	Desmin-related myofibrillar myopathy (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Congenital diaphragmatic hernia (1)
-	-	1	Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type (1)
-	-	1	Dilated cardiomyopathy 1I (1)
1	-	-	Myofibrillar myopathy (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)
-	-	1	Neurogenic scapuloperoneal syndrome, Kaeser type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.0041	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.90	P
Vest4		0.59
MPC		0.011
ClinPred		0.017	T
GERP RS		3.7
Varity_R		0.40
gMVP		0.62
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.053
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.030		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: rs41272699; hg19: chr2-220284876; COSMIC: COSV99059323; COSMIC: COSV99059323;