rs1280095100

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_001267550.2(TTN):c.37734C>T(p.Ala12578Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 1,433,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 18)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.140

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 2-178658135-G-A is Benign according to our data. Variant chr2-178658135-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 535231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.14 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	UniProt
TTN	NM_001267550.2	MANE Select	c.37734C>T	p.Ala12578Ala	synonymous	Exon 186 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.34522+870C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.31741+870C>T		intron	N/A	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.37734C>T	p.Ala12578Ala	synonymous	Exon 186 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.37734C>T	p.Ala12578Ala	synonymous	Exon 186 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.37458C>T	p.Ala12486Ala	synonymous	Exon 184 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.0000208

AC:

AN:

144098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000731

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

221644

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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

AF:

0.00000628

AC:

AN:

1433444

Hom.:

Cov.:

AF XY:

0.00000701

AC XY:

AN XY:

713230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32530

American (AMR)

AF:

0.00

AC:

AN:

42594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.00000723

AC:

AN:

1107254

Other (OTH)

AF:

0.00

AC:

AN:

59684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000208

AC:

AN:

144098

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

69948

show subpopulations

African (AFR)

AF:

0.0000266

AC:

AN:

37590

American (AMR)

AF:

0.0000731

AC:

AN:

13678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5046

South Asian (SAS)

AF:

0.00

AC:

AN:

4386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66778

Other (OTH)

AF:

0.00

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.5

(source)

DANN

Benign

0.76

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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