2-178581595-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.66673G>A(p.Asp22225Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,612,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D22225D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 1.85

Publications

5 publications found

Variant links:

COSMIC-nc: COSV104640754

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022572488).

BP6

Variant 2-178581595-C-T is Benign according to our data. Variant chr2-178581595-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47238.

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	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.66673G>A	p.Asp22225Asn	missense	Exon 316 of 363	NP_001254479.2
TTN	NM_001256850.1		c.61750G>A	p.Asp20584Asn	missense	Exon 266 of 313	NP_001243779.1
TTN	NM_133378.4		c.58969G>A	p.Asp19657Asn	missense	Exon 265 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.66673G>A	p.Asp22225Asn	missense	Exon 316 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.66517G>A	p.Asp22173Asn	missense	Exon 314 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.66397G>A	p.Asp22133Asn	missense	Exon 314 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000165

AC:

AN:

247950

AF XY:

0.000164

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000339

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000366

AC:

535

AN:

1460486

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

253

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33412

American (AMR)

AF:

0.0000224

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000452

AC:

502

AN:

1111162

Other (OTH)

AF:

0.000464

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000309

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41566

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000589

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000288

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000483

AC:

ExAC

AF:

0.000174

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000416

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

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

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.85

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.83

M_CAP

Benign

0.023

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.72

PhyloP100

1.9

PrimateAI

Benign

0.44

PROVEAN

Benign

1.3

REVEL

Benign

0.065

Sift

Benign

1.0

Polyphen

0.0

Vest4

0.24

MVP

0.048

MPC

0.082

ClinPred

0.029

GERP RS

3.0

Mutation Taster

=78/22

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over