rs7585334

Positions:

• chr2-178756224-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.11252G>A​(p.Gly3751Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.9 in 1,594,874 control chromosomes in the GnomAD database, including 650,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58115 hom., cov: 33)
  • Exomes 𝑓: 0.90 (592684 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Scores: Splicing: ADA: 0.002052
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.78

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

Verdict is Benign. Variant got -19 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=8.103962E-7).
• BP6: Variant 2-178756224-C-T is Benign according to our data. Variant chr2-178756224-C-T is described in ClinVar as [Benign]. Clinvar id is 47852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178756224-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11252G>A	p.Gly3751Asp	missense_variant, splice_region_variant	46/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10303+2760G>A		intron_variant		ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.11252G>A	p.Gly3751Asp	missense_variant, splice_region_variant	46/363	5	NM_001267550.2	ENSP00000467141	P1
TTN	ENST00000360870.10	c.10303+2760G>A		intron_variant		5	NM_133379.5	ENSP00000354117
TTN-AS1	ENST00000659121.1	n.1224-42C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132390 AN: 152096 Hom.: 58094 Cov.: 33

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.895

GnomAD3 exomes AF: 0.838 AC: 203686 AN: 242962 Hom.: 87621 AF XY: 0.850 AC XY: 111850 AN XY: 131650

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 0.755

Gnomad SAS exome AF: 0.787

Gnomad FIN exome AF: 0.891

Gnomad NFE exome AF: 0.930

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.903 AC: 1303069 AN: 1442660 Hom.: 592684 Cov.: 30 AF XY: 0.902 AC XY: 644760 AN XY: 714838

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.585

Gnomad4 ASJ exome AF: 0.917

Gnomad4 EAS exome AF: 0.783

Gnomad4 SAS exome AF: 0.796

Gnomad4 FIN exome AF: 0.888

Gnomad4 NFE exome AF: 0.931

Gnomad4 OTH exome AF: 0.896

GnomAD4 genome AF: 0.870 AC: 132452 AN: 152214 Hom.: 58115 Cov.: 33 AF XY: 0.865 AC XY: 64327 AN XY: 74408

Gnomad4 AFR AF: 0.834

Gnomad4 AMR AF: 0.718

Gnomad4 ASJ AF: 0.918

Gnomad4 EAS AF: 0.781

Gnomad4 SAS AF: 0.791

Gnomad4 FIN AF: 0.890

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.897

Alfa AF: 0.919 Hom.: 149882

Bravo AF: 0.854

TwinsUK AF: 0.931 AC: 3453

ALSPAC AF: 0.930 AC: 3584

ESP6500AA AF: 0.840 AC: 3266

ESP6500EA AF: 0.932 AC: 7723

ExAC AF: 0.849 AC: 102606

Asia WGS AF: 0.795 AC: 2768 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.91
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	8.1e-7	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.55	P;P;P;P;P;P;P
PROVEAN	Benign	-0.84	.;N
REVEL	Benign	0.037
Sift	Benign	1.0	.;T
Vest4		0.14
MPC		0.11
ClinPred		0.014	T
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
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: rs7585334; hg19: chr2-179620951;