dbSNP rs56273463: TTN:p.Arg33738Cys (chr2-178535403-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):c.101212C>T(p.Arg33738Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,613,814 control chromosomes in the GnomAD database, including 86 homozygotes. 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. R33738H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0060 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0089 ( 82 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:25

Conservation

PhyloP100: 7.97

Publications

13 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008329332).

BP6

Variant 2-178535403-G-A is Benign according to our data. Variant chr2-178535403-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47633.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00598 (911/152246) while in subpopulation NFE AF = 0.01 (680/68020). AF 95% confidence interval is 0.00937. There are 4 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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	HGVSp	Effect	Exon Rank	Protein	UniProt
TTN	NM_001267550.2	MANE Select	c.101212C>T	p.Arg33738Cys	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.96289C>T	p.Arg32097Cys	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.93508C>T	p.Arg31170Cys	missense	Exon 307 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTN	ENST00000589042.5	TSL:5 MANE Select	c.101212C>T	p.Arg33738Cys	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.101056C>T	p.Arg33686Cys	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.100936C>T	p.Arg33646Cys	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.00599

AC:

912

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00510

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00562

AC:

1399

AN:

248932

AF XY:

0.00561

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00397

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00418

Gnomad NFE exome

AF:

0.00866

Gnomad OTH exome

AF:

0.00895

GnomAD4 exome

AF:

0.00895

AC:

13077

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00878

AC XY:

6385

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33472

American (AMR)

AF:

0.00436

AC:

195

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00409

AC:

107

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00262

AC:

226

AN:

86258

European-Finnish (FIN)

AF:

0.00493

AC:

263

AN:

53348

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0105

AC:

11714

AN:

1111804

Other (OTH)

AF:

0.00840

AC:

507

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

867

1735

2602

3470

4337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.00598

AC:

911

AN:

152246

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

412

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41542

American (AMR)

AF:

0.00536

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00510

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

680

AN:

68020

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00754

Hom.:

Bravo

AF:

0.00579

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00230

AC:

ESP6500EA

AF:

0.00976

AC:

ExAC

AF:

0.00563

AC:

681

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00834

EpiControl

AF:

0.00907

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (7)

Atrial fibrillation;C0878544:Cardiomyopathy (1)

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

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

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1G (1)

Early-onset myopathy with fatal cardiomyopathy (1)

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

Tibial muscular dystrophy (1)

TTN-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Benign

0.97

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.3

PhyloP100

8.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.46

Sift

Benign

0.035

Polyphen

1.0

Vest4

0.46

MVP

0.72

MPC

0.54

ClinPred

0.029

GERP RS

5.5

Mutation Taster

=86/14

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