NM_001267550.2:c.107393C>T

Variant names:

• chr2-178527733-G-A
• rs886038722
• NM_001267550.2:c.107393C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.107393C>T​(p.Pro35798Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,599,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P35798T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.75
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18871641).
• BP6: Variant 2-178527733-G-A is Benign according to our data. Variant chr2-178527733-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262344.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.107393C>T	p.Pro35798Leu	missense	Exon 362 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.102470C>T	p.Pro34157Leu	missense	Exon 312 of 313	NP_001243779.1
	TTN	NM_133378.4		c.99689C>T	p.Pro33230Leu	missense	Exon 311 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.107393C>T	p.Pro35798Leu	missense	Exon 362 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.107237C>T	p.Pro35746Leu	missense	Exon 360 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.107117C>T	p.Pro35706Leu	missense	Exon 360 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237428 AF XY: 0.00000777

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000935

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000691 AC: 10 AN: 1447608 Hom.: 0 Cov.: 32 AF XY: 0.00000696 AC XY: 5 AN XY: 718312

African (AFR) AF: 0.00 AC: 0 AN: 33176

American (AMR) AF: 0.00 AC: 0 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25158

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 84426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000816 AC: 9 AN: 1103002

Other (OTH) AF: 0.0000167 AC: 1 AN: 59814

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000783 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.85
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D
Polyphen		0.0070	B
Vest4		0.45
MutPred		0.34		Loss of disorder (P = 0.0599)
MVP		0.43
MPC		0.087
ClinPred		0.15	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs886038722; hg19: chr2-179392460;