2-178551701-T-A

Variant names:

• chr2-178551701-T-A
• rs376494747
• NM_001267550.2:c.91199A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.91199A>T​(p.Tyr30400Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. Y30400C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.731
• Publications: 0 publications found

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-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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04162076).
• BP6: Variant 2-178551701-T-A is Benign according to our data. Variant chr2-178551701-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202976.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.91199A>T	p.Tyr30400Phe	missense	Exon 335 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.86276A>T	p.Tyr28759Phe	missense	Exon 285 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.83495A>T	p.Tyr27832Phe	missense	Exon 284 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.91199A>T	p.Tyr30400Phe	missense	Exon 335 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.91043A>T	p.Tyr30348Phe	missense	Exon 333 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.90923A>T	p.Tyr30308Phe	missense	Exon 333 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000725 AC: 18 AN: 248378 AF XY: 0.0000668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461062 Hom.: 0 Cov.: 33 AF XY: 0.0000550 AC XY: 40 AN XY: 726736

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111466

Other (OTH) AF: 0.000199 AC: 12 AN: 60346

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.9
DANN	Benign	0.87
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	N
PhyloP100		0.73
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.063
Sift	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.47		Loss of phosphorylation at Y28759 (P = 0.0382)
MVP		0.17
MPC		0.077
ClinPred		0.037	T
GERP RS		0.48
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs376494747; hg19: chr2-179416428;