2-178723594-T-C

Variant names:

• chr2-178723594-T-C
• rs786205314
• NM_001267550.2:c.21506A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.21506A>G​(p.Asn7169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N7169T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 1 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]

ENSG00000267784 (HGNC:):

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10124767).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.21506A>G	p.Asn7169Ser	missense	Exon 74 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.20555A>G	p.Asn6852Ser	missense	Exon 72 of 313	NP_001243779.1
	TTN	NM_133378.4		c.17774A>G	p.Asn5925Ser	missense	Exon 71 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.21506A>G	p.Asn7169Ser	missense	Exon 74 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.21506A>G	p.Asn7169Ser	missense	Exon 74 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.21230A>G	p.Asn7077Ser	missense	Exon 72 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 247918 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461050 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726788

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111554

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.89
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.12
Sift	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.061
MPC		0.067
ClinPred		0.020	T
GERP RS		5.2
Mutation Taster		=93/7	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: rs786205314; hg19: chr2-179588321;