chr2-178662773-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001267550.2(TTN):c.36830C>T(p.Ala12277Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000084 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.638

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015921652).

BP6

Variant 2-178662773-G-A is Benign according to our data. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178662773-G-A is described in CliVar as Likely_benign. Clinvar id is 238755.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.36830C>T	p.Ala12277Val	missense_variant	Exon 175 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.36830C>T	p.Ala12277Val	missense_variant	Exon 175 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

134780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000152

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:

0.0000636

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000519

AC:

AN:

55920

AF XY:

0.000713

show subpopulations

Gnomad AFR exome

AF:

0.000568

Gnomad AMR exome

AF:

0.000557

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000127

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000837

AC:

102

AN:

1218788

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

609500

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000252

AC:

AN:

27820

American (AMR)

AF:

0.000166

AC:

AN:

36136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21694

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37466

South Asian (SAS)

AF:

0.000775

AC:

AN:

74812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39490

Middle Eastern (MID)

AF:

0.000853

AC:

AN:

3516

European-Non Finnish (NFE)

AF:

0.0000248

AC:

AN:

926268

Other (OTH)

AF:

0.0000775

AC:

AN:

51586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

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:

0.000119

AC:

AN:

134866

Hom.:

Cov.:

AF XY:

0.0000927

AC XY:

AN XY:

64702

show subpopulations

African (AFR)

AF:

0.000281

AC:

AN:

35590

American (AMR)

AF:

0.000152

AC:

AN:

13194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3250

East Asian (EAS)

AF:

0.00

AC:

AN:

4480

South Asian (SAS)

AF:

0.00

AC:

AN:

3814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000636

AC:

AN:

62898

Other (OTH)

AF:

0.00

AC:

AN:

1768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.6

(source)

DANN

Benign

0.72

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.00091

LIST_S2

Benign

0.21

M_CAP

Benign

0.026

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

PhyloP100

-0.64

Vest4

0.030

MVP

0.25

MPC

0.083

ClinPred

0.0058

GERP RS

3.3

Mutation Taster

=93/7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over