chr2-178771192-C-T

Variant names:

• chr2-178771192-C-T
• rs13011633
• NM_001267550.2:c.8116+19G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.8116+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,613,536 control chromosomes in the GnomAD database, including 929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (73 hom., cov: 32)
  • Exomes 𝑓: 0.031 (856 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.349
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-178771192-C-T is Benign according to our data. Variant chr2-178771192-C-T is described in ClinVar as Benign. ClinVar VariationId is 137825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0256 (3893/152256) while in subpopulation AMR AF = 0.0377 (576/15294). AF 95% confidence interval is 0.0359. There are 73 homozygotes in GnomAd4. There are 1839 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 73 AD,AR gene

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.8116+19G>A		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.8116+19G>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.8116+19G>A		intron	N/A	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.8116+19G>A		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.8116+19G>A		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.7840+19G>A		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3892 AN: 152138 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00582

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0248 AC: 6214 AN: 250790 AF XY: 0.0252

Gnomad AFR exome AF: 0.00424

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0285

Gnomad NFE exome AF: 0.0370

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0314 AC: 45850 AN: 1461280 Hom.: 856 Cov.: 34 AF XY: 0.0309 AC XY: 22489 AN XY: 726966

African (AFR) AF: 0.00589 AC: 197 AN: 33454

American (AMR) AF: 0.0234 AC: 1046 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 384 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39654

South Asian (SAS) AF: 0.00917 AC: 791 AN: 86230

European-Finnish (FIN) AF: 0.0273 AC: 1457 AN: 53406

Middle Eastern (MID) AF: 0.0462 AC: 252 AN: 5460

European-Non Finnish (NFE) AF: 0.0360 AC: 40014 AN: 1111888

Other (OTH) AF: 0.0282 AC: 1703 AN: 60354

GnomAD4 genome AF: 0.0256 AC: 3893 AN: 152256 Hom.: 73 Cov.: 32 AF XY: 0.0247 AC XY: 1839 AN XY: 74450

African (AFR) AF: 0.00580 AC: 241 AN: 41544

American (AMR) AF: 0.0377 AC: 576 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10606

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0371 AC: 2524 AN: 68008

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0323 Hom.: 25

Bravo AF: 0.0267

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.85
DANN	Benign	0.63
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs13011633; hg19: chr2-179635919; COSMIC: COSV60129187;