NM_001267550.2:c.36830C>A

Variant names:

• chr2-178662773-G-T
• rs878854300
• NM_001267550.2:c.36830C>A

Variant summary

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

The NM_001267550.2(TTN):​c.36830C>A​(p.Ala12277Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12277V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0000098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.638
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03259021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.36830C>A	p.Ala12277Glu	missense_variant	Exon 175 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.36830C>A	p.Ala12277Glu	missense_variant	Exon 175 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000371 AC: 5 AN: 134788 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00111

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: 0.0000894 AC: 5 AN: 55920 AF XY: 0.000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000635

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000985 AC: 12 AN: 1218796 Hom.: 0 Cov.: 17 AF XY: 0.0000148 AC XY: 9 AN XY: 609506

African (AFR) AF: 0.00 AC: 0 AN: 27820

American (AMR) AF: 0.00 AC: 0 AN: 36138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21694

East Asian (EAS) AF: 0.000320 AC: 12 AN: 37466

South Asian (SAS) AF: 0.00 AC: 0 AN: 74820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 926266

Other (OTH) AF: 0.00 AC: 0 AN: 51586

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000371 AC: 5 AN: 134874 Hom.: 0 Cov.: 20 AF XY: 0.0000309 AC XY: 2 AN XY: 64704

African (AFR) AF: 0.00 AC: 0 AN: 35592

American (AMR) AF: 0.00 AC: 0 AN: 13194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3250

East Asian (EAS) AF: 0.00112 AC: 5 AN: 4480

South Asian (SAS) AF: 0.00 AC: 0 AN: 3820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62898

Other (OTH) AF: 0.00 AC: 0 AN: 1768

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.8
DANN	Benign	0.69
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.64
Vest4		0.088
MVP		0.18
MPC		0.099
ClinPred		0.014	T
GERP RS		3.3
Mutation Taster		=86/14	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: rs878854300; hg19: chr2-179527500;