rs373587801

Variant names:

• chr2-178594238-G-T
• rs373587801
• NM_001267550.2:c.58155C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001267550.2(TTN):​c.58155C>A​(p.Pro19385Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000872 in 1,605,956 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P19385P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.110
• Publications: 1 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-178594238-G-T is Benign according to our data. Variant chr2-178594238-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 228111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.11 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.58155C>A	p.Pro19385Pro	synonymous	Exon 297 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.53232C>A	p.Pro17744Pro	synonymous	Exon 247 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.50451C>A	p.Pro16817Pro	synonymous	Exon 246 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.58155C>A	p.Pro19385Pro	synonymous	Exon 297 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.57999C>A	p.Pro19333Pro	synonymous	Exon 295 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.57879C>A	p.Pro19293Pro	synonymous	Exon 295 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000108 AC: 26 AN: 241348 AF XY: 0.0000612

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.0000308

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: 0.00

GnomAD4 exome AF: 0.0000440 AC: 64 AN: 1453798 Hom.: 0 Cov.: 34 AF XY: 0.0000387 AC XY: 28 AN XY: 722904

African (AFR) AF: 0.00165 AC: 54 AN: 32752

American (AMR) AF: 0.0000708 AC: 3 AN: 42374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 84154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109988

Other (OTH) AF: 0.000117 AC: 7 AN: 60050

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74370

African (AFR) AF: 0.00173 AC: 72 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000597 Hom.: 0

Bravo AF: 0.000620

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.52
DANN	Benign	0.80
PhyloP100		-0.11
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373587801; hg19: chr2-179458965; COSMIC: COSV104645599;