chr2-178559697-A-G

Variant names:

• chr2-178559697-A-G
• rs727504959
• NM_001267550.2:c.86435T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001267550.2(TTN):​c.86435T>C​(p.Ile28812Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,607,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I28812V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.27
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.86435T>C	p.Ile28812Thr	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.81512T>C	p.Ile27171Thr	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.78731T>C	p.Ile26244Thr	missense	Exon 275 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.86435T>C	p.Ile28812Thr	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.86279T>C	p.Ile28760Thr	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.86159T>C	p.Ile28720Thr	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 4 AN: 242466 AF XY: 0.0000305

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1455426 Hom.: 0 Cov.: 32 AF XY: 0.0000180 AC XY: 13 AN XY: 723474

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.0000226 AC: 1 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85024

European-Finnish (FIN) AF: 0.0000943 AC: 5 AN: 52996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1108682

Other (OTH) AF: 0.0000499 AC: 3 AN: 60104

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74438

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000571 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Benign	0.85
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Polyphen		0.12	B
Vest4		0.31
MutPred		0.81		Gain of glycosylation at I27171 (P = 0.0103)
MVP		0.76
MPC		0.14
ClinPred		0.44	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	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: rs727504959; hg19: chr2-179424424;