NM_001267550.2:c.18029-19G>C

Variant names:

• chr2-178730390-C-G
• rs17076
• NM_001267550.2:c.18029-19G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.18029-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,555,784 control chromosomes in the GnomAD database, including 38,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4869 hom., cov: 33)
  • Exomes 𝑓: 0.20 (33602 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.145
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-178730390-C-G is Benign according to our data. Variant chr2-178730390-C-G is described in ClinVar as [Benign]. Clinvar id is 137838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.18029-19G>C		intron_variant	Intron 61 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.18029-19G>C		intron_variant	Intron 61 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35153 AN: 151870 Hom.: 4859 Cov.: 33

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.249 AC: 50529 AN: 203110 AF XY: 0.241

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.665

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.200 AC: 281234 AN: 1403796 Hom.: 33602 Cov.: 45 AF XY: 0.201 AC XY: 138926 AN XY: 692738

African (AFR) AF: 0.261 AC: 8037 AN: 30768

American (AMR) AF: 0.362 AC: 11808 AN: 32630

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 3835 AN: 23326

East Asian (EAS) AF: 0.661 AC: 25653 AN: 38784

South Asian (SAS) AF: 0.245 AC: 18917 AN: 77248

European-Finnish (FIN) AF: 0.146 AC: 7562 AN: 51682

Middle Eastern (MID) AF: 0.221 AC: 1209 AN: 5478

European-Non Finnish (NFE) AF: 0.177 AC: 191834 AN: 1086220

Other (OTH) AF: 0.215 AC: 12379 AN: 57660

GnomAD4 genome AF: 0.232 AC: 35206 AN: 151988 Hom.: 4869 Cov.: 33 AF XY: 0.234 AC XY: 17395 AN XY: 74272

African (AFR) AF: 0.256 AC: 10607 AN: 41452

American (AMR) AF: 0.300 AC: 4582 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3359 AN: 5158

South Asian (SAS) AF: 0.255 AC: 1223 AN: 4804

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10580

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12308 AN: 67956

Other (OTH) AF: 0.227 AC: 478 AN: 2108

Alfa AF: 0.187 Hom.: 568

Bravo AF: 0.251

Asia WGS AF: 0.431 AC: 1500 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Aug 16, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 31, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tibial muscular dystrophy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.1
DANN	Benign	0.49
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs17076; hg19: chr2-179595117; COSMIC: COSV60101809; COSMIC: COSV60101809;