rs145996491

Variant names:

• chr2-178748608-G-A
• rs145996491
• NM_001267550.2:c.11311+4516C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178748608-G-A
• chr2-178748608-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001267550.2(TTN):​c.11311+4516C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,613,024 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: -0.00700
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054371953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.11311+4516C>T		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.11311+4516C>T		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 56 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000961 AC: 24 AN: 249710 AF XY: 0.0000741

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1460972 Hom.: 0 Cov.: 35 AF XY: 0.0000303 AC XY: 22 AN XY: 726802

African (AFR) AF: 0.00123 AC: 41 AN: 33430

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111446

Other (OTH) AF: 0.0000497 AC: 3 AN: 60344

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74326

African (AFR) AF: 0.00135 AC: 56 AN: 41500

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

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: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Pro4598Ser vari ant in TTN has been identified by our laboratory in 1 Black individual with isol ated right atrial enlargement and 1 Black individual with HCM (LMM unpublished d ata). It has also been identified in 0.1% (6/4406) of African American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs145996491). Computational analyses are limited or unavailable for this vari ant. While the frequency of this variant suggests that it is more likely benign, it is too low to confidently rule out a disease-causing role. Additional inform ation is needed to fully assess the clinical significance of this variant. -

TTN-related disorder Uncertain:1

Oct 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTN c.13792C>T variant is predicted to result in the amino acid substitution p.Pro4598Ser. This variant has been reported in an individual with dilated cardiomyopathy (Table S6, Haas et al. 2015. PubMed ID: 25163546). This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179613335-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Other:1

Oct 07, 2013

GeneDx

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.79
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.0070
PROVEAN	Benign	0.30	N
REVEL	Benign	0.036
Sift	Benign	0.24	T
Sift4G	Benign	0.85	T
Polyphen		0.0020	B
Vest4		0.069
MVP		0.067
ClinPred		0.0067	T
GERP RS		-0.61
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs145996491; hg19: chr2-179613335;