2-178526912-C-CT

Variant names:

• chr2-178526912-C-CT
• rs11424072
• NM_001267550.2:c.*99dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.*99dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11668 hom., cov: 0)
  • Exomes 𝑓: 0.26 (40006 hom.)
• Consequence: TTN NM_001267550.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.858

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 -16 ACMG points.

• BP6: Variant 2-178526912-C-CT is Benign according to our data. Variant chr2-178526912-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 332674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.*99dupA		3_prime_UTR_variant	Exon 363 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042	c.*99dupA		3_prime_UTR_variant	Exon 363 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54601 AN: 151822 Hom.: 11619 Cov.: 0

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.327

GnomAD4 exome AF: 0.256 AC: 262040 AN: 1024052 Hom.: 40006 Cov.: 13 AF XY: 0.260 AC XY: 130352 AN XY: 501178

African (AFR) AF: 0.538 AC: 12250 AN: 22766

American (AMR) AF: 0.404 AC: 7166 AN: 17734

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 4613 AN: 16892

East Asian (EAS) AF: 0.685 AC: 22577 AN: 32954

South Asian (SAS) AF: 0.487 AC: 22621 AN: 46434

European-Finnish (FIN) AF: 0.270 AC: 9642 AN: 35706

Middle Eastern (MID) AF: 0.286 AC: 919 AN: 3216

European-Non Finnish (NFE) AF: 0.211 AC: 169281 AN: 804064

Other (OTH) AF: 0.293 AC: 12971 AN: 44286

GnomAD4 genome AF: 0.360 AC: 54712 AN: 151940 Hom.: 11668 Cov.: 0 AF XY: 0.370 AC XY: 27468 AN XY: 74252

African (AFR) AF: 0.535 AC: 22150 AN: 41406

American (AMR) AF: 0.384 AC: 5861 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 987 AN: 3466

East Asian (EAS) AF: 0.700 AC: 3621 AN: 5170

South Asian (SAS) AF: 0.514 AC: 2477 AN: 4820

European-Finnish (FIN) AF: 0.285 AC: 3003 AN: 10554

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15311 AN: 67944

Other (OTH) AF: 0.335 AC: 707 AN: 2110

Alfa AF: 0.112 Hom.: 129

Bravo AF: 0.377

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset myopathy with fatal cardiomyopathy Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

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

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism (auto)

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: rs11424072; hg19: chr2-179391639; COSMIC: COSV59866051; COSMIC: COSV59866051;