Genetic Variant TTN:p.Val29796Met (chr2-178553619-C-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.89386G>A(p.Val29796Met) variant causes a missense change. The variant allele was found at a frequency of 0.000965 in 1,613,874 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V29796V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 4 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:16

Conservation

PhyloP100: 4.99

Publications

12 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009649873).

BP6

Variant 2-178553619-C-T is Benign according to our data. Variant chr2-178553619-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96314.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000749 (114/152294) while in subpopulation SAS AF = 0.00311 (15/4830). AF 95% confidence interval is 0.00191. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 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.89386G>A	p.Val29796Met	missense	Exon 334 of 363	NP_001254479.2
TTN	NM_001256850.1		c.84463G>A	p.Val28155Met	missense	Exon 284 of 313	NP_001243779.1
TTN	NM_133378.4		c.81682G>A	p.Val27228Met	missense	Exon 283 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.89386G>A	p.Val29796Met	missense	Exon 334 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.89230G>A	p.Val29744Met	missense	Exon 332 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.89110G>A	p.Val29704Met	missense	Exon 332 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00128

AC:

319

AN:

248568

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00329

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000756

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.000987

AC:

1443

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

822

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00519

AC:

448

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000712

AC:

792

AN:

1111786

Other (OTH)

AF:

0.00123

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000749

AC:

114

AN:

152294

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41576

American (AMR)

AF:

0.000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68012

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000900

Hom.:

Bravo

AF:

0.000699

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.00132

AC:

159

Asia WGS

AF:

0.00173

AC:

AN:

3476

EpiCase

AF:

0.00125

EpiControl

AF:

0.000889

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Hypertrophic cardiomyopathy (2)

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)

Hypotonia;C0349588:Short stature;C0454644:Delayed speech and language development;C0746674:Generalized muscle weakness;C2315100:Failure to thrive;C3687424:Abnormal speech pattern;C4021753:Abnormality of the immune system (1)

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

Primary dilated cardiomyopathy (1)

Tibial muscular dystrophy (1)

TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.020

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

PhyloP100

5.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Uncertain

0.011

Polyphen

1.0

Vest4

0.43

MVP

0.52

MPC

0.47

ClinPred

0.054

GERP RS

5.6

Mutation Taster

=97/3

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