rs12998857

Variant names:

• chr2-178668882-A-C
• rs12998857
• NM_001267550.2:c.35545+491T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001267550.2(TTN):​c.35545+491T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 149,686 control chromosomes in the GnomAD database, including 2,210 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2210 hom., cov: 30)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 7 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.35545+491T>G		intron_variant	Intron 159 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.35545+491T>G		intron_variant	Intron 159 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22589 AN: 149576 Hom.: 2208 Cov.: 30

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.158

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.151 AC: 22593 AN: 149686 Hom.: 2210 Cov.: 30 AF XY: 0.154 AC XY: 11250 AN XY: 72992

African (AFR) AF: 0.0634 AC: 2589 AN: 40850

American (AMR) AF: 0.159 AC: 2387 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 678 AN: 3444

East Asian (EAS) AF: 0.448 AC: 2262 AN: 5048

South Asian (SAS) AF: 0.265 AC: 1236 AN: 4658

European-Finnish (FIN) AF: 0.132 AC: 1342 AN: 10156

Middle Eastern (MID) AF: 0.171 AC: 49 AN: 286

European-Non Finnish (NFE) AF: 0.168 AC: 11288 AN: 67288

Other (OTH) AF: 0.162 AC: 333 AN: 2054

Alfa AF: 0.169 Hom.: 2321

Bravo AF: 0.150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.030
DANN	Benign	0.59
PhyloP100		-0.085
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

Other links and lift over

dbSNP: rs12998857; hg19: chr2-179533609; COSMIC: COSV59918687; COSMIC: COSV59918687;