rs568086259

Positions:

• chr2-178658278-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):​c.37705G>A​(p.Val12569Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (132 hom., cov: 10)
  • Exomes 𝑓: 0.0047 (231 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.143

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004136145).
• BP6: Variant 2-178658278-C-T is Benign according to our data. Variant chr2-178658278-C-T is described in ClinVar as [Benign]. Clinvar id is 238760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178658278-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.37705G>A	p.Val12569Ile	missense_variant	185/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+13777C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.37705G>A	p.Val12569Ile	missense_variant	185/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+60597C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2569 AN: 79136 Hom.: 123 Cov.: 10 FAILED QC

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.000432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000549

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0135

Gnomad NFE AF: 0.000516

Gnomad OTH AF: 0.0305

GnomAD3 exomes AF: 0.0174 AC: 872 AN: 50002 Hom.: 147 AF XY: 0.0146 AC XY: 370 AN XY: 25346

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00961

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000933

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.00673

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00472 AC: 3814 AN: 807342 Hom.: 231 Cov.: 11 AF XY: 0.00423 AC XY: 1742 AN XY: 411764

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000514

Gnomad4 FIN exome AF: 0.0000320

Gnomad4 NFE exome AF: 0.000391

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0328 AC: 2601 AN: 79236 Hom.: 132 Cov.: 10 AF XY: 0.0331 AC XY: 1216 AN XY: 36750

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.000432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000546

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000516

Gnomad4 OTH AF: 0.0296

Alfa AF: 0.0327 Hom.: 35

ExAC AF: 0.00384 AC: 89

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.0
DANN	Benign	0.77
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
Vest4		0.12
MPC		0.076
ClinPred		0.0025	T
GERP RS		3.2

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: rs568086259; hg19: chr2-179523005;