NM_001267550.2:c.40222+20_40222+23dupTATA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001267550.2(TTN):c.40222+20_40222+23dupTATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0065 in 730,512 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 21)

Exomes 𝑓: 0.0039 ( 1 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: -0.212

Publications

4 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 -10 ACMG points.

BP6

Variant 2-178647040-G-GTATA is Benign according to our data. Variant chr2-178647040-G-GTATA is described in ClinVar as Likely_benign. ClinVar VariationId is 1193112.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0173 (2480/143300) while in subpopulation EAS AF = 0.0423 (206/4868). AF 95% confidence interval is 0.0376. There are 29 homozygotes in GnomAd4. There are 1251 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

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	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.40222+20_40222+23dupTATA	intron	N/A	NP_001254479.2
TTN	NM_001256850.1		c.35375-1014_35375-1011dupTATA	intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.32594-1014_32594-1011dupTATA	intron	N/A	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.40222+23_40222+24insTATA	intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.40222+23_40222+24insTATA	intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.39946+23_39946+24insTATA	intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2484

AN:

143234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0392

Gnomad AMI

AF:

0.00227

Gnomad AMR

AF:

0.00929

Gnomad ASJ

AF:

0.0160

Gnomad EAS

AF:

0.0426

Gnomad SAS

AF:

0.00560

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.0102

Gnomad NFE

AF:

0.00504

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.0121

AC:

186

AN:

15314

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00230

Gnomad EAS exome

AF:

0.0167

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.00321

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.00386

AC:

2269

AN:

587212

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

1162

AN XY:

291970

show subpopulations

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

African (AFR)

AF:

0.0147

AC:

186

AN:

12662

American (AMR)

AF:

0.00345

AC:

AN:

7240

Ashkenazi Jewish (ASJ)

AF:

0.00758

AC:

AN:

9768

East Asian (EAS)

AF:

0.0187

AC:

359

AN:

19242

South Asian (SAS)

AF:

0.00200

AC:

AN:

10484

European-Finnish (FIN)

AF:

0.0124

AC:

346

AN:

27996

Middle Eastern (MID)

AF:

0.00376

AC:

AN:

1862

European-Non Finnish (NFE)

AF:

0.00240

AC:

1133

AN:

472814

Other (OTH)

AF:

0.00469

AC:

118

AN:

25144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.341

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.0173

AC:

2480

AN:

143300

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1251

AN XY:

69516

show subpopulations

African (AFR)

AF:

0.0390

AC:

1550

AN:

39696

American (AMR)

AF:

0.00928

AC:

133

AN:

14326

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

AN:

3374

East Asian (EAS)

AF:

0.0423

AC:

206

AN:

4868

South Asian (SAS)

AF:

0.00563

AC:

AN:

4444

European-Finnish (FIN)

AF:

0.0176

AC:

152

AN:

8648

Middle Eastern (MID)

AF:

0.00741

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.00504

AC:

327

AN:

64836

Other (OTH)

AF:

0.0148

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00232

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 21, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

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

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over