dbSNP rs72646885: TTN:p.Ser23226Gly (chr2-178576568-T-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):c.69676A>G(p.Ser23226Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,613,606 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 70 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:31

Conservation

PhyloP100: 7.97

Publications

20 publications found

Variant links:

COSMIC-nc: COSV107413235

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: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 2-178576568-T-C is Benign according to our data. Variant chr2-178576568-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00575 (875/152254) while in subpopulation SAS AF = 0.00871 (42/4820). AF 95% confidence interval is 0.00744. There are 8 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.69676A>G	p.Ser23226Gly	missense	Exon 325 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.64753A>G	p.Ser21585Gly	missense	Exon 275 of 313	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.61972A>G	p.Ser20658Gly	missense	Exon 274 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.69676A>G	p.Ser23226Gly	missense	Exon 325 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.69520A>G	p.Ser23174Gly	missense	Exon 323 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.69400A>G	p.Ser23134Gly	missense	Exon 323 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

877

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00803

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00755

AC:

1875

AN:

248248

AF XY:

0.00828

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00429

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00218

Gnomad NFE exome

AF:

0.00845

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00716

AC:

10461

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00746

AC XY:

5425

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33452

American (AMR)

AF:

0.00483

AC:

216

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

821

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0116

AC:

996

AN:

86230

European-Finnish (FIN)

AF:

0.00287

AC:

153

AN:

53392

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00681

AC:

7568

AN:

1111654

Other (OTH)

AF:

0.00925

AC:

558

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

682

1363

2045

2726

3408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.00575

AC:

875

AN:

152254

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41588

American (AMR)

AF:

0.00445

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00871

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00800

AC:

544

AN:

67988

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

137

183

229

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:

0.00797

Hom.:

Bravo

AF:

0.00570

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00103

AC:

ESP6500EA

AF:

0.00918

AC:

ExAC

AF:

0.00751

AC:

907

Asia WGS

AF:

0.00491

AC:

AN:

3476

EpiCase

AF:

0.0106

EpiControl

AF:

0.0100

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (12)

not provided (5)

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

Early-onset myopathy with fatal cardiomyopathy (2)

Myopathy, myofibrillar, 9, with early respiratory failure (2)

Tibial muscular dystrophy (2)

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

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1G (1)

Hypertrophic cardiomyopathy;C0042514:Ventricular tachycardia;na:Familial dilated cardiomyopathy and peripheral neuropathy (1)

TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Benign

0.84

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0046

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.6

PhyloP100

8.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.0080

Polyphen

1.0

Vest4

0.44

MVP

0.38

MPC

0.44

ClinPred

0.073

GERP RS

4.6

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.72

Position offset: 0

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

Computational scores

Splicing

Publications

Other links and lift over