2-178526912-CTTTT-CTTTTTT

Variant names:

• chr2-178526912-C-CTT
• rs11424072
• NM_001267550.2:c.*98_*99dupAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001267550.2(TTN):​c.*98_*99dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: TTN NM_001267550.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.858
• 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]

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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00236 (358/152006) while in subpopulation AFR AF = 0.00792 (328/41436). AF 95% confidence interval is 0.00721. There are 0 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.*98_*99dupAA		3_prime_UTR	Exon 363 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.*98_*99dupAA		3_prime_UTR	Exon 313 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.*98_*99dupAA		3_prime_UTR	Exon 312 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.*98_*99dupAA		3_prime_UTR	Exon 363 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.*98_*99dupAA		3_prime_UTR	Exon 361 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.*98_*99dupAA		3_prime_UTR	Exon 361 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 358 AN: 151888 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000589

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000288 AC: 295 AN: 1025440 Hom.: 0 Cov.: 13 AF XY: 0.000269 AC XY: 135 AN XY: 501892

African (AFR) AF: 0.00725 AC: 165 AN: 22770

American (AMR) AF: 0.000845 AC: 15 AN: 17748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16912

East Asian (EAS) AF: 0.000212 AC: 7 AN: 32946

South Asian (SAS) AF: 0.000236 AC: 11 AN: 46522

European-Finnish (FIN) AF: 0.0000839 AC: 3 AN: 35750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3220

European-Non Finnish (NFE) AF: 0.0000832 AC: 67 AN: 805238

Other (OTH) AF: 0.000609 AC: 27 AN: 44334

GnomAD4 genome AF: 0.00236 AC: 358 AN: 152006 Hom.: 0 Cov.: 0 AF XY: 0.00234 AC XY: 174 AN XY: 74298

African (AFR) AF: 0.00792 AC: 328 AN: 41436

American (AMR) AF: 0.00157 AC: 24 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67960

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00 Hom.: 129

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11424072; hg19: chr2-179391639;