rs150223722

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):​c.38929C>T​(p.Pro12977Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,611,716 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 5 hom., cov: 31)
Exomes 𝑓: 0.0064 ( 61 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.120
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-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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00516212).
BP6
Variant 2-178652878-G-A is Benign according to our data. Variant chr2-178652878-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178652878-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00395 (601/152160) while in subpopulation SAS AF= 0.0207 (100/4820). AF 95% confidence interval is 0.0175. There are 5 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.38929C>T p.Pro12977Ser missense_variant Exon 200 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.38929C>T p.Pro12977Ser missense_variant Exon 200 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.00393
AC:
598
AN:
152042
Hom.:
5
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00236
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0201
Gnomad FIN
AF:
0.00170
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00577
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00597
AC:
1457
AN:
244164
Hom.:
17
AF XY:
0.00701
AC XY:
933
AN XY:
133074
show subpopulations
Gnomad AFR exome
AF:
0.000956
Gnomad AMR exome
AF:
0.00162
Gnomad ASJ exome
AF:
0.000102
Gnomad EAS exome
AF:
0.000112
Gnomad SAS exome
AF:
0.0227
Gnomad FIN exome
AF:
0.00121
Gnomad NFE exome
AF:
0.00577
Gnomad OTH exome
AF:
0.00594
GnomAD4 exome
AF:
0.00639
AC:
9324
AN:
1459556
Hom.:
61
Cov.:
34
AF XY:
0.00691
AC XY:
5020
AN XY:
726064
show subpopulations
Gnomad4 AFR exome
AF:
0.000962
Gnomad4 AMR exome
AF:
0.00198
Gnomad4 ASJ exome
AF:
0.000231
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0232
Gnomad4 FIN exome
AF:
0.00131
Gnomad4 NFE exome
AF:
0.00606
Gnomad4 OTH exome
AF:
0.00565
GnomAD4 genome
AF:
0.00395
AC:
601
AN:
152160
Hom.:
5
Cov.:
31
AF XY:
0.00390
AC XY:
290
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00104
Gnomad4 AMR
AF:
0.00236
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0207
Gnomad4 FIN
AF:
0.00170
Gnomad4 NFE
AF:
0.00577
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00323
Hom.:
0
Bravo
AF:
0.00327
TwinsUK
AF:
0.00539
AC:
20
ALSPAC
AF:
0.00623
AC:
24
ESP6500AA
AF:
0.000571
AC:
1
ESP6500EA
AF:
0.00678
AC:
27
ExAC
AF:
0.00636
AC:
765
Asia WGS
AF:
0.0120
AC:
40
AN:
3478
EpiCase
AF:
0.00639
EpiControl
AF:
0.00528

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:7
Jun 19, 2018
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:1
Mar 10, 2020
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Sep 10, 2021
Genome-Nilou Lab
Significance: 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
-0.53
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
16
DANN
Benign
0.57
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.73
T
MetaRNN
Benign
0.0052
T
Vest4
0.17
MVP
0.84
GERP RS
3.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150223722; hg19: chr2-179517605; API