Genetic Variant NM_001267550.2:c.62275G>A (chr2-178589450-C-T) – 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.62275G>A(p.Glu20759Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000265 in 1,613,386 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. E20759E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 7 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 4.08

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.009337664).

BP6

Variant 2-178589450-C-T is Benign according to our data. Variant chr2-178589450-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165915.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000223 (34/152170) while in subpopulation SAS AF = 0.00664 (32/4822). AF 95% confidence interval is 0.00483. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 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.62275G>A	p.Glu20759Lys	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
TTN	NM_001256850.1		c.57352G>A	p.Glu19118Lys	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
TTN	NM_133378.4		c.54571G>A	p.Glu18191Lys	missense	Exon 253 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.62275G>A	p.Glu20759Lys	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
TTN	ENST00000446966.2	TSL:1	c.62119G>A	p.Glu20707Lys	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
TTN	ENST00000436599.2	TSL:1	c.61999G>A	p.Glu20667Lys	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000568

AC:

141

AN:

248124

AF XY:

0.000721

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000269

AC:

393

AN:

1461216

Hom.:

Cov.:

AF XY:

0.000384

AC XY:

279

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.00432

AC:

373

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111660

Other (OTH)

AF:

0.000282

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000223

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00664

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

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:

0.0000673

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000588

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

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)

not provided (1)

Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.053

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.6

PhyloP100

4.1

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.22

Sift

Benign

0.063

Polyphen

0.84

Vest4

0.53

MutPred

0.54

Gain of methylation at E19118 (P = 0.0284)

MVP

0.31

MPC

0.17

ClinPred

0.047

GERP RS

6.0

Mutation Taster

=80/20

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