NM_001267550.2:c.44848G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001267550.2(TTN):c.44848G>A(p.Asp14950Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000224 in 1,605,128 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D14950E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.18

Publications

3 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20133013).

BP6

Variant 2-178622735-C-T is Benign according to our data. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834. Variant chr2-178622735-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404834.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.44848G>A	p.Asp14950Asn	missense_variant	Exon 243 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.44848G>A	p.Asp14950Asn	missense_variant	Exon 243 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151578

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000210

AC:

AN:

238044

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.000140

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000580

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1453434

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

722304

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33244

American (AMR)

AF:

0.00

AC:

AN:

43928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39260

South Asian (SAS)

AF:

0.00

AC:

AN:

84456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1107976

Other (OTH)

AF:

0.00

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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

AF:

0.0000659

AC:

AN:

151694

Hom.:

Cov.:

AF XY:

0.0000675

AC XY:

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000196

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67816

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000332

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 27, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TTN-related disorder

Uncertain:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TTN c.44848G>A variant is predicted to result in the amino acid substitution p.Asp14950Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Jan 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D;.;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.20

T;T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

.;.;.;M;.;.;M

PhyloP100

7.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.7

D;D;.;.;D;D;.

REVEL

Uncertain

0.36

Sift

Benign

0.063

T;D;.;.;D;D;.

Polyphen

1.0

.;.;.;D;.;.;D

Vest4

0.37

MutPred

0.58

.;.;.;Loss of loop (P = 0.1242);.;.;Loss of loop (P = 0.1242);

MVP

0.27

MPC

0.40

ClinPred

0.58

GERP RS

5.5

Mutation Taster

=58/42

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over