chr2-178526815-G-C

Variant names:

Variant summary

Our verdict is The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Moderate

The NM_001267550.2(TTN):c.*197C>G variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000528 (AC=28) in the gnomAD database across 529,824 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000059. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.76). Variant has been reported in ClinVar as Uncertain Significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

TTN
NM_001267550.2 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:5

Conservation

PhyloP100: 9.76

Publications

1 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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy 1G
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
myopathy, myofibrillar, 9, with early respiratory failure
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
early-onset myopathy with fatal cardiomyopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
TTN-related myopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
tibial muscular dystrophy
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2J
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
TTN-related myopathy, dominant-negative TTNsv
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, G2P
congenital myopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
familial hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: G2P
hereditary skeletal muscle disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy 9
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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

new If you want to explore the variant's impact on the transcript NM_001267550.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 points.

PM2

Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000059 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000161 by highest known P/LP ClinVar AF 0.000161) — PM2 supporting.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TTN	NM_001267550.2	MANE Select	c.*197C>G	3_prime_UTR	Exon 363 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.*197C>G	3_prime_UTR	Exon 313 of 313	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.*197C>G	3_prime_UTR	Exon 312 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TTN	ENST00000589042.5	TSL:5 MANE Select	c.*197C>G	3_prime_UTR	Exon 363 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.*197C>G	3_prime_UTR	Exon 361 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.*197C>G	3_prime_UTR	Exon 361 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

377646

Hom.:

Cov.:

AF XY:

0.0000717

AC XY:

AN XY:

195244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11436

American (AMR)

AF:

0.00

AC:

AN:

14146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11970

East Asian (EAS)

AF:

0.00

AC:

AN:

28898

South Asian (SAS)

AF:

0.00

AC:

AN:

25094

European-Finnish (FIN)

AF:

0.0000397

AC:

AN:

25168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1710

European-Non Finnish (NFE)

AF:

0.0000888

AC:

AN:

236566

Other (OTH)

AF:

0.0000441

AC:

AN:

22658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

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:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

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

TOPMed (Bravo)

AF:

0.0000189

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.000141

AC:

AN:

21310

Hom.:

Case/control cohorts

Cohort

Cases

Controls

SCHEMA

(Schizophrenia)

2 / 47322AF: 0.0000422636

1 / 79184AF: 0.0000126288

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2J (1)

Dilated cardiomyopathy 1G (1)

Early-onset myopathy with fatal cardiomyopathy (1)

Myopathy, myofibrillar, 9, with early respiratory failure (1)

Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

9.8

AlphaGenome AVI

Uncertain

(source)

GPN-Star LLR

-5.5

(source)

GPN-Star score

5.5

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over