2-178658775-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_001267550.2(TTN):c.37473G>C(p.Pro12491Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000082 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000037 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.98

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-178658775-C-G is Benign according to our data. Variant chr2-178658775-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 413094.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.98 with no splicing effect.

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.37473G>C	p.Pro12491Pro	synonymous	Exon 183 of 363	NP_001254479.2
TTN	NM_001256850.1		c.34522+230G>C		intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.31741+230G>C		intron	N/A	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.37473G>C	p.Pro12491Pro	synonymous	Exon 183 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.37473G>C	p.Pro12491Pro	synonymous	Exon 183 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.37197G>C	p.Pro12399Pro	synonymous	Exon 181 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0000748

AC:

AN:

146984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

237418

AF XY:

0.00000776

show subpopulations

Gnomad AFR exome

AF:

0.000216

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000373

AC:

AN:

1449244

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

721092

show subpopulations

African (AFR)

AF:

0.000782

AC:

AN:

33240

American (AMR)

AF:

0.00

AC:

AN:

44398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.0000584

AC:

AN:

85600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103488

Other (OTH)

AF:

0.000351

AC:

AN:

59790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000816

AC:

AN:

147100

Hom.:

Cov.:

AF XY:

0.0000559

AC XY:

AN XY:

71552

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

40052

American (AMR)

AF:

0.00

AC:

AN:

14552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

5034

South Asian (SAS)

AF:

0.00

AC:

AN:

4432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66390

Other (OTH)

AF:

0.00

AC:

AN:

2026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.607

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:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.022

(source)

DANN

Benign

0.63

PhyloP100

-3.0

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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