rs200495902

Variant names:

• chr2-178654766-G-A
• rs200495902
• NM_001267550.2:c.38185C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):​c.38185C>T​(p.Pro12729Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P12729P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., cov: 8)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070644617).
• BP6: Variant 2-178654766-G-A is Benign according to our data. Variant chr2-178654766-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 192167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.38185C>T	p.Pro12729Ser	missense_variant	Exon 191 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.38185C>T	p.Pro12729Ser	missense_variant	Exon 191 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000496 AC: 3 AN: 60494 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000965

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000554

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00163 AC: 55 AN: 33688 AF XY: 0.00204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000469

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000397 AC: 239 AN: 601868 Hom.: 0 Cov.: 8 AF XY: 0.000560 AC XY: 173 AN XY: 308836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000719 AC: 1 AN: 13900

American (AMR) AF: 0.000169 AC: 3 AN: 17792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14404

East Asian (EAS) AF: 0.00 AC: 0 AN: 30030

South Asian (SAS) AF: 0.00372 AC: 163 AN: 43786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42646

Middle Eastern (MID) AF: 0.000920 AC: 2 AN: 2174

European-Non Finnish (NFE) AF: 0.000155 AC: 63 AN: 407014

Other (OTH) AF: 0.000232 AC: 7 AN: 30122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000496 AC: 3 AN: 60540 Hom.: 0 Cov.: 8 AF XY: 0.000110 AC XY: 3 AN XY: 27312

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11888

American (AMR) AF: 0.00 AC: 0 AN: 4188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1844

East Asian (EAS) AF: 0.00 AC: 0 AN: 1618

South Asian (SAS) AF: 0.000960 AC: 1 AN: 1042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.0000554 AC: 2 AN: 36088

Other (OTH) AF: 0.00 AC: 0 AN: 754

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000468493), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.67
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.45	T;.
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0071	T;T
PhyloP100		1.4
Vest4		0.20
MVP		0.44
GERP RS		0.83
Mutation Taster		=96/4	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: rs200495902; hg19: chr2-179519493;