chr2-178526912-C-CT

Position:

• chr2-178526912-C-CT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.*99_*100insA 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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TTN	NM_001267550.2	c.*99_*100insA		3_prime_UTR_variant	363/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.219+3284dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.*99_*100insA		3_prime_UTR_variant	363/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+3284dup		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.538

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.685

Gnomad4 SAS exome AF: 0.487

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.293

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

Gnomad4 AFR AF: 0.535

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.700

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.335

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Tibial muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 18, 2019

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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;