TTN p.Pro12729Ser

Variant names:

• chr2-178654766-G-A
• rs200495902
• NM_001267550.2:c.38185C>T
• TTN p.Pro12729Ser

Your query was ambiguous. Multiple possible variants found:

• chr2-178654766-G-A
• chr2-178654764-CGG-AGA
• chr2-178654764-CGG-GGA
• chr2-178654764-CGG-TGA
• chr2-178654764-CGG-ACT
• chr2-178654764-CGG-GCT

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BP4_StrongBP6_Strong

The NM_001267550.2(TTN):c.38185C>T (p.Pro12729Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. No reliable population frequency data is available for this variant in the gnomAD database. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P12729= (synonymous): Likely_benign (ClinVar VariationId 3024677, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., cov: 8)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43
• 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• TTN-related myopathy, dominant-negative TTNsv

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• familial hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TTN NM_001267550.2	MANE Select	c.38185C>T p.Pro12729Ser	missense	Exon 191 of 363	Prot: NP_001254479.2 UniProt:
	TTN NM_001256850.1		c.34523-2225C>T	intron	Intron 156 of 312	Prot: NP_001243779.1 UniProt:
	TTN NM_133378.4		c.31742-2225C>T	intron	Intron 155 of 311	Prot: NP_596869.4 UniProt:

TTN NM_001267550.2

MANE Select

HGVSc / HGVSpc.38185C>Tp.Pro12729Ser

Exon rankExon 191 of 363

missense

Prot: NP_001254479.2UniProt: Q8WZ42-12

TTN NM_001256850.1

HGVSc / HGVSpc.34523-2225C>T

Exon rankIntron 156 of 312

intron

Prot: NP_001243779.1UniProt: Q8WZ42-1

TTN NM_133378.4

HGVSc / HGVSpc.31742-2225C>T

Exon rankIntron 155 of 311

intron

Prot: NP_596869.4UniProt: Q8WZ42-11

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TTN ENST00000589042.5	TSL:5MANE Select	c.38185C>T p.Pro12729Ser	missense	Exon 191 of 363	Prot: ENSP00000467141.1 UniProt:
	TTN ENST00000446966.2	TSL:1	c.38185C>T p.Pro12729Ser	missense	Exon 191 of 361	Prot: ENSP00000408004.2 UniProt:
	TTN ENST00000436599.2	TSL:1	c.37909C>T p.Pro12637Ser	missense	Exon 189 of 361	Prot: ENSP00000405517.2 UniProt:

TTN ENST00000589042.5

TSL:5MANE Select

HGVSc / HGVSpc.38185C>Tp.Pro12729Ser

Exon rankExon 191 of 363

missense

Prot: ENSP00000467141.1UniProt: Q8WZ42-12

TTN ENST00000446966.2

TSL:1

HGVSc / HGVSpc.38185C>Tp.Pro12729Ser

Exon rankExon 191 of 361

missense

Prot: ENSP00000408004.2UniProt: A0A1B0GXE3

TTN ENST00000436599.2

TSL:1

HGVSc / HGVSpc.37909C>Tp.Pro12637Ser

Exon rankExon 189 of 361

missense

Prot: ENSP00000405517.2UniProt: A0A0C4DG59

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000496	AC:3	Hom:0	AN:60494	Cov:8
GnomAD2 exomes	AF: 0.00163	AC:55	Hom:	AN:33688	Cov:
GnomAD4 exome Warning	AF: 0.000397	AC:239	Hom:0	AN:601868	Cov:8
GnomAD4 genome Warning	AF: 0.0000496	AC:3	Hom:0	AN:60540	Cov:8
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000107	3	28090	0.000175	5	28552

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.67
FATHMM_MKL	Benign	0.062	N
FuncVEP CTI	Benign	0.028
GPN-Star LLR	N/A	-3.3
GPN-Star score	N/A	3.3
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0071	T
Mutation Taster	N/A	96/4	polymorphism
PhyloP100	Benign	1.4

Showing 14 of 14 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200495902;

hg19: chr2-179519493;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar