Genetic Variant TTN:p.Pro13156Thr (chr2-178651534-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.39466C>A(p.Pro13156Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,612,820 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P13156P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 8 hom. )

Consequence

TTN
NM_001267550.2 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:14

Conservation

PhyloP100: 3.01

Publications

7 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:

LOC124906100 (HGNC:):

LOC124906100 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017347962).

BP6

Variant 2-178651534-G-T is Benign according to our data. Variant chr2-178651534-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178221.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000767 (1121/1460640) while in subpopulation MID AF = 0.00278 (16/5754). AF 95% confidence interval is 0.00189. There are 8 homozygotes in GnomAdExome4. There are 607 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 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	UniProt
TTN	NM_001267550.2	MANE Select	c.39466C>A	p.Pro13156Thr	missense splice_region	Exon 207 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.34945C>A	p.Pro11649Thr	missense splice_region	Exon 162 of 313	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.32164C>A	p.Pro10722Thr	missense splice_region	Exon 161 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTN	ENST00000589042.5	TSL:5 MANE Select	c.39466C>A	p.Pro13156Thr	missense splice_region	Exon 207 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.39466C>A	p.Pro13156Thr	missense splice_region	Exon 207 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.39190C>A	p.Pro13064Thr	missense splice_region	Exon 205 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000634

AC:

157

AN:

247548

AF XY:

0.000692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000795

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000767

AC:

1121

AN:

1460640

Hom.:

Cov.:

AF XY:

0.000835

AC XY:

607

AN XY:

726562

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33398

American (AMR)

AF:

0.000247

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00214

AC:

184

AN:

86054

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000780

AC:

867

AN:

1111462

Other (OTH)

AF:

0.000431

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000493

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41530

American (AMR)

AF:

0.000262

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000417

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000612

AC:

ExAC

AF:

0.000704

AC:

EpiCase

AF:

0.000710

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (4)

Autosomal recessive limb-girdle muscular dystrophy type 2J (1)

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

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1G (1)

Early-onset myopathy with fatal cardiomyopathy (1)

Myopathy, myofibrillar, 9, with early respiratory failure (1)

Primary familial hypertrophic cardiomyopathy (1)

Supraventricular tachycardia;C0878544:Cardiomyopathy (1)

Tibial muscular dystrophy (1)

TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.84

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.050

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.5

PhyloP100

3.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.44

Sift

Uncertain

0.027

Polyphen

0.75

Vest4

0.24

MVP

0.45

MPC

0.29

ClinPred

0.11

GERP RS

5.2

PromoterAI

0.021

Neutral

(source)

Mutation Taster

=74/26

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

Computational scores

Splicing

Publications

Other links and lift over