rs900028908

Variant names:

• chr2-178662793-T-C
• rs900028908
• NM_001267550.2:c.36810A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001267550.2(TTN):​c.36810A>G​(p.Glu12270Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00020 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0190
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-178662793-T-C is Benign according to our data. Variant chr2-178662793-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 467075.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.36810A>G	p.Glu12270Glu	synonymous_variant	Exon 175 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.36810A>G	p.Glu12270Glu	synonymous_variant	Exon 175 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 15 AN: 139714 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000730

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000186

Gnomad OTH AF: 0.00108

GnomAD2 exomes AF: 0.000129 AC: 7 AN: 54440 AF XY: 0.000183

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.0000929

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000199 AC: 221 AN: 1109108 Hom.: 1 Cov.: 14 AF XY: 0.000196 AC XY: 109 AN XY: 556434

African (AFR) AF: 0.0000392 AC: 1 AN: 25480

American (AMR) AF: 0.0000626 AC: 2 AN: 31932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19950

East Asian (EAS) AF: 0.00 AC: 0 AN: 36390

South Asian (SAS) AF: 0.00 AC: 0 AN: 69822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3304

European-Non Finnish (NFE) AF: 0.000251 AC: 209 AN: 833192

Other (OTH) AF: 0.000188 AC: 9 AN: 47848

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000107 AC: 15 AN: 139714 Hom.: 0 Cov.: 22 AF XY: 0.0000594 AC XY: 4 AN XY: 67310

African (AFR) AF: 0.00 AC: 0 AN: 37110

American (AMR) AF: 0.0000730 AC: 1 AN: 13698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 4660

South Asian (SAS) AF: 0.00 AC: 0 AN: 4112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.000186 AC: 12 AN: 64426

Other (OTH) AF: 0.00108 AC: 2 AN: 1858

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000117

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.68
PhyloP100		0.019
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs900028908; hg19: chr2-179527520;