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

Our verdict: Benign. The variant received -14 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BP6: 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).
• BS1: GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0334 vs gene BS1 threshold 0.015.
• BS2: ≥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	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.84394A>T	p.Ile28132Leu	missense	Exon 284 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.81613A>T	p.Ile27205Leu	missense	Exon 283 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.89317A>T	p.Ile29773Leu	missense	Exon 334 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.89161A>T	p.Ile29721Leu	missense	Exon 332 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.89041A>T	p.Ile29681Leu	missense	Exon 332 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152186 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00253 AC: 629 AN: 248516 AF XY: 0.00209

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00103 AC: 1512 AN: 1461568 Hom.: 27 Cov.: 33 AF XY: 0.000897 AC XY: 652 AN XY: 727064

African (AFR) AF: 0.0351 AC: 1175 AN: 33476

American (AMR) AF: 0.00208 AC: 93 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111792

Other (OTH) AF: 0.00250 AC: 151 AN: 60368

GnomAD4 genome AF: 0.0101 AC: 1537 AN: 152304 Hom.: 20 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74474

African (AFR) AF: 0.0343 AC: 1426 AN: 41570

American (AMR) AF: 0.00504 AC: 77 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

TOPMed (Bravo) AF: 0.0119

ALFA (dbGaP/dbSNP Allele Frequency Aggregator) AF: 0.00216 AC: 252 AN: 116576 Hom.: 5

Local populations

ABraOM SABE-WGS-1171 AF: 0.00769 AC: 18 AN: 2342 Hom.: 0

ESP6500 (Exome Variant Server) AF: 0.0104 AC: 129 AN: 12372

European American AF: 0.00 AC: 0 AN: 8354

African American AF: 0.0321 AC: 129 AN: 4018

GenomeAsia100K AF: 0.00173 AC: 6 AN: 3478

Oceania AF: 0.00 AC: 0 AN: 148 Hom.: 0

North-East Asia AF: 0.00 AC: 0 AN: 702 Hom.: 0

South-East Asia AF: 0.00 AC: 0 AN: 692 Hom.: 0

South Asia AF: 0.00 AC: 0 AN: 1448 Hom.: 0

Africa AF: 0.0288 AC: 6 AN: 208 Hom.: 0

America AF: 0.00 AC: 0 AN: 52 Hom.: 0

West Eurasia AF: 0.00 AC: 0 AN: 228 Hom.: 0

Qatari Genome AF: 0.0170 AC: 3 AN: 176

Turkish Variome AF: 0.000177 AC: 1 AN: 5174 Hom.: 0

UK10K AF: 0.000132 AC: 1 AN: 7562

TwinsUK AF: 0.000280 AC: 1 AN: 3574

ALSPAC AF: 0.00 AC: 0 AN: 3854

Case/control cohorts

Cohort

Cases

Controls

ASC (Autism)

1 / 9622AF: 0.000103928

0 / 10426AF: 0

BipEx (Bipolar disorder (including schizoaffective))

1 / 28418AF: 0.0000351890

3 / 28828AF: 0.000104065

Epi25 (Epilepsy)

129 / 41956AF: 0.00307465

230 / 66876AF: 0.00343920

SCHEMA (Schizophrenia)

1158 / 121994AF: 0.00949227

1983 / 191254AF: 0.0103684

Allele 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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N
PhyloP100		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
FuncVEP CTI	Benign	0.00049
AlphaGenome AVI	Uncertain	19
GPN-Star LLR		-3.9
GPN-Star score		3.9
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2
Pangolin (max)	Benign	0.0

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.

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