rs77853750

Variant names:

• chr2-178553688-T-A
• rs77853750
• NM_001267550.2:c.89317A>T
• TTN p.Ile29773Leu

Your query was ambiguous. Multiple possible variants found:

• chr2-178553688-T-A
• chr2-178553688-T-G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_ModerateBP6_Strong

The NM_001267550.2(TTN):c.89317A>T (p.Ile29773Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00189 (AC=3,049) in the gnomAD database across 1,613,872 control chromosomes, including 47 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0334. In-silico predictor (REVEL) 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 (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 2.71
• Publications: 6 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 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 (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (26/26 total B/LB).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0334 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 47.; Very high cumulative gnomAD AC = 3049 (any gene).

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.89317A>T p.Ile29773Leu	missense	Exon 334 of 363	Prot: NP_001254479.2 UniProt:
	TTN NM_001256850.1		c.84394A>T p.Ile28132Leu	missense	Exon 284 of 313	Prot: NP_001243779.1 UniProt:
	TTN NM_133378.4		c.81613A>T p.Ile27205Leu	missense	Exon 283 of 312	Prot: NP_596869.4 UniProt:

TTN NM_001267550.2

MANE Select

HGVSc / HGVSpc.89317A>Tp.Ile29773Leu

Exon rankExon 334 of 363

missense

Prot: NP_001254479.2UniProt: Q8WZ42-12

TTN NM_001256850.1

HGVSc / HGVSpc.84394A>Tp.Ile28132Leu

Exon rankExon 284 of 313

missense

Prot: NP_001243779.1UniProt: Q8WZ42-1

TTN NM_133378.4

HGVSc / HGVSpc.81613A>Tp.Ile27205Leu

Exon rankExon 283 of 312

missense

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.89317A>T p.Ile29773Leu	missense	Exon 334 of 363	Prot: ENSP00000467141.1 UniProt:
	TTN ENST00000446966.2	TSL:1	c.89161A>T p.Ile29721Leu	missense	Exon 332 of 361	Prot: ENSP00000408004.2 UniProt:
	TTN ENST00000436599.2	TSL:1	c.89041A>T p.Ile29681Leu	missense	Exon 332 of 361	Prot: ENSP00000405517.2 UniProt:

TTN ENST00000589042.5

TSL:5MANE Select

HGVSc / HGVSpc.89317A>Tp.Ile29773Leu

Exon rankExon 334 of 363

missense

Prot: ENSP00000467141.1UniProt: Q8WZ42-12

TTN ENST00000446966.2

TSL:1

HGVSc / HGVSpc.89161A>Tp.Ile29721Leu

Exon rankExon 332 of 361

missense

Prot: ENSP00000408004.2UniProt: A0A1B0GXE3

TTN ENST00000436599.2

TSL:1

HGVSc / HGVSpc.89041A>Tp.Ile29681Leu

Exon rankExon 332 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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0101	AC:1538	Hom:21	AN:152186	Cov:33
GnomAD2 exomes	AF: 0.00253	AC:629	Hom:	AN:248516	Cov:
GnomAD4 exome	AF: 0.00103	AC:1512	Hom:27	AN:1461568	Cov:33
GnomAD4 genome	AF: 0.0101	AC:1537	Hom:20	AN:152304	Cov:33
TOPMed (Bravo)	AF: 0.0119	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00216	AC:252	Hom:5	AN:116576	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00769	AC:18	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0104	AC:129	Hom:	AN:12372	Cov:
GenomeAsia100K	AF: 0.00173	AC:6	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.0170	AC:3	Hom:	AN:176	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5174	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9622	0.00 *	0	10426
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28418	0.000104	3	28828
Epi25(Epilepsy)	0.00307	129	41956	0.00344	230	66876
SCHEMA(Schizophrenia)	0.00949	1158	121994	0.0104	1983	191254

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.69
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.88	D
FuncVEP CTI	Benign	0.00049
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	91/9	polymorphism
MutationAssessor	Benign	0.32	N
PhyloP100	Benign	2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.076
Sift	Benign	0.71	T
VESM-3B	Benign	-3.6

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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: rs77853750;

hg19: chr2-179418415;

COSMIC: COSV115018788;

COSMIC: COSV115018788;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar