Genetic Variant TTN:p.Pro3990Leu (chr2-178741264-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):c.11969C>T(p.Pro3990Leu) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,613,806 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., cov: 32)

Exomes 𝑓: 0.010 ( 99 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 5.19

Publications

18 publications found

Variant links:

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061140656).

BP6

Variant 2-178741264-G-A is Benign according to our data. Variant chr2-178741264-G-A is described in ClinVar as Benign. ClinVar VariationId is 47814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0064 (974/152288) while in subpopulation NFE AF = 0.0115 (779/68022). AF 95% confidence interval is 0.0108. There are 4 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.11969C>T	p.Pro3990Leu	missense	Exon 48 of 363	NP_001254479.2
TTN	NM_001256850.1		c.11018C>T	p.Pro3673Leu	missense	Exon 46 of 313	NP_001243779.1
TTN	NM_133437.4		c.11456C>T	p.Pro3819Leu	missense	Exon 46 of 192	NP_597681.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.11969C>T	p.Pro3990Leu	missense	Exon 48 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.11969C>T	p.Pro3990Leu	missense	Exon 48 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.11693C>T	p.Pro3898Leu	missense	Exon 46 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

974

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00651

AC:

1618

AN:

248430

AF XY:

0.00662

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00293

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.00514

GnomAD4 exome

AF:

0.0104

AC:

15223

AN:

1461518

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

7420

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33474

American (AMR)

AF:

0.00304

AC:

136

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00417

AC:

109

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000510

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00398

AC:

212

AN:

53304

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0127

AC:

14125

AN:

1111812

Other (OTH)

AF:

0.00868

AC:

524

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

964

1928

2892

3856

4820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

544

1088

1632

2176

2720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00640

AC:

974

AN:

152288

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

427

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41570

American (AMR)

AF:

0.00281

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0115

AC:

779

AN:

68022

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00923

Hom.:

Bravo

AF:

0.00657

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00316

AC:

ESP6500EA

AF:

0.0118

AC:

ExAC

AF:

0.00700

AC:

846

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0102

EpiControl

AF:

0.00942

ClinVar

Significance: Benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 23, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro3752Leu in exon 45B of TTN: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence and has been identified in 1.1% (73/6658) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs33971253). Pro3752Leu in exon 45B of TTN (rs33971253; allele frequ ency = 1.1%, 73/6658) **

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 29, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:6

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 31, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Benign:1

Dec 03, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy;C0039240:Supraventricular tachycardia

Benign:1

Mar 25, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tibial muscular dystrophy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Nov 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.71

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.90

PhyloP100

5.2

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.24

Sift

Benign

0.26

Vest4

0.28

MVP

0.38

MPC

0.17

ClinPred

0.030

GERP RS

5.9

Mutation Taster

=65/35

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over