rs201888760

chr2-178741088-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001267550.2(TTN):c.12145C>T(p.Pro4049Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 0.258

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0190306).
• BP6: Variant 2-178741088-G-A is Benign according to our data. Variant chr2-178741088-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47817.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4, Benign=1}. Variant chr2-178741088-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.12145C>T	p.Pro4049Ser	missense_variant	48/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.12145C>T	p.Pro4049Ser	missense_variant	48/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1134-1793G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000387 AC: 96 AN: 248296 Hom.: 1 AF XY: 0.000379 AC XY: 51 AN XY: 134678

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000526

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1461576 Hom.: 1 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 727074

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74458

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000365 Hom.: 1

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000480 AC: 58

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TTN: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 20, 2018	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TTN p.Pro3878Ser variant was identified in 1 of 144 proband chromosomes (frequency: 0.0069) from an individual with dilated cardiomyopathy who also carried a TTN truncating mutation (Franaszczyk_2017_PMID:28045975). The variant was identified in dbSNP (ID: rs201888760) and ClinVar (classified as likely benign by Biesecker Lab and GeneDx and uncertain significance by Invitae, Athena Diagnostics Inc, Laboratory for Molecular Medicine and EGL Genetic Diagnostics). The variant was identified in control databases in 104 of 279690 chromosomes (1 homozygous) at a frequency of 0.0003718 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 11 of 10328 chromosomes (freq: 0.001065), Other in 7 of 7110 chromosomes (freq: 0.000985), European (non-Finnish) in 63 of 127606 chromosomes (freq: 0.000494), South Asian in 13 of 30594 chromosomes (freq: 0.000425), Latino in 6 of 35360 chromosomes (freq: 0.00017) and African in 4 of 24182 chromosomes (freq: 0.000165), but was not observed in the East Asian, or European (Finnish) populations. The p.Pro3878 residue has limited species conservation data and computational analyses (BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2012

The Pro3811Ser variant in TTN has been identified in 1/6622 European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). Conservation and computational tools are limited or unavailable for this variant. Additional information is needed to assess the cli nical significance of this variant. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2017

- -

TTN-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The TTN c.12145C>T variant is predicted to result in the amino acid substitution p.Pro4049Ser. This variant was reported along with a truncating TTN variant in an individual with dilated cardiomyopathy; however, no additional studies were performed to help assess the pathogenicity of this variant (Table S4, Franaszczyk et al. 2017. PubMed ID: 28045975). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote in this population database (http://gnomad.broadinstitute.org/variant/2-179605815-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 08, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	1.8
Dann	Benign	0.67
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.78	T;T;.;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.019	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D;.;.;D;D;.
REVEL	Benign	0.065
Sift	Pathogenic	0.0	D;.;.;T;D;.
Vest4		0.042
MVP		0.040
MPC		0.084
ClinPred		0.019	T
GERP RS		-0.66

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: rs201888760; hg19: chr2-179605815; COSMIC: COSV60084222; COSMIC: COSV60084222;