chr2-178526912-CT-C

Variant names:

• chr2-178526912-CT-C
• rs11424072
• NM_001267550.2:c.*99delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001267550.2(TTN):​c.*99delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (18 hom., cov: 0)
  • Exomes 𝑓: 0.023 (331 hom.)
• Consequence: TTN NM_001267550.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-178526912-CT-C is Benign according to our data. Variant chr2-178526912-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1204371.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2453/152002) while in subpopulation NFE AF = 0.0229 (1557/67958). AF 95% confidence interval is 0.022. There are 18 homozygotes in GnomAd4. There are 1230 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.*99delA		3_prime_UTR_variant	Exon 363 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.*99delA		3_prime_UTR_variant	Exon 363 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2455 AN: 151884 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.00508

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0231 AC: 23720 AN: 1025538 Hom.: 331 Cov.: 13 AF XY: 0.0225 AC XY: 11315 AN XY: 501946

African (AFR) AF: 0.00408 AC: 93 AN: 22800

American (AMR) AF: 0.0157 AC: 278 AN: 17762

Ashkenazi Jewish (ASJ) AF: 0.00414 AC: 70 AN: 16916

East Asian (EAS) AF: 0.000152 AC: 5 AN: 32982

South Asian (SAS) AF: 0.00614 AC: 286 AN: 46558

European-Finnish (FIN) AF: 0.0243 AC: 870 AN: 35756

Middle Eastern (MID) AF: 0.0115 AC: 37 AN: 3222

European-Non Finnish (NFE) AF: 0.0263 AC: 21202 AN: 805190

Other (OTH) AF: 0.0198 AC: 879 AN: 44352

GnomAD4 genome AF: 0.0161 AC: 2453 AN: 152002 Hom.: 18 Cov.: 0 AF XY: 0.0166 AC XY: 1230 AN XY: 74294

African (AFR) AF: 0.00504 AC: 209 AN: 41438

American (AMR) AF: 0.0162 AC: 248 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

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

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4822

European-Finnish (FIN) AF: 0.0307 AC: 324 AN: 10554

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1557 AN: 67958

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.00309 Hom.: 129

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

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
PhyloP100		0.86
Mutation Taster		=100/0	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: rs11424072; hg19: chr2-179391639;