2-178730390-C-G

Variant names:

• chr2-178730390-C-G
• rs17076
• NM_001267550.2:c.18029-19G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000589042.5(TTN):​c.18029-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,555,784 control chromosomes in the GnomAD database, including 38,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4869 hom., cov: 33)
  • Exomes 𝑓: 0.20 (33602 hom.)
• Consequence: TTN ENST00000589042.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.145
• Publications: 12 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=-0.93).
• BP6: Variant 2-178730390-C-G is Benign according to our data. Variant chr2-178730390-C-G is described in ClinVar as Benign. ClinVar VariationId is 137838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.18029-19G>C		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.17078-19G>C		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.14297-19G>C		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.18029-19G>C		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.18029-19G>C		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.17753-19G>C		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35153 AN: 151870 Hom.: 4859 Cov.: 33

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.249 AC: 50529 AN: 203110 AF XY: 0.241

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.665

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.200 AC: 281234 AN: 1403796 Hom.: 33602 Cov.: 45 AF XY: 0.201 AC XY: 138926 AN XY: 692738

African (AFR) AF: 0.261 AC: 8037 AN: 30768

American (AMR) AF: 0.362 AC: 11808 AN: 32630

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 3835 AN: 23326

East Asian (EAS) AF: 0.661 AC: 25653 AN: 38784

South Asian (SAS) AF: 0.245 AC: 18917 AN: 77248

European-Finnish (FIN) AF: 0.146 AC: 7562 AN: 51682

Middle Eastern (MID) AF: 0.221 AC: 1209 AN: 5478

European-Non Finnish (NFE) AF: 0.177 AC: 191834 AN: 1086220

Other (OTH) AF: 0.215 AC: 12379 AN: 57660

GnomAD4 genome AF: 0.232 AC: 35206 AN: 151988 Hom.: 4869 Cov.: 33 AF XY: 0.234 AC XY: 17395 AN XY: 74272

African (AFR) AF: 0.256 AC: 10607 AN: 41452

American (AMR) AF: 0.300 AC: 4582 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3359 AN: 5158

South Asian (SAS) AF: 0.255 AC: 1223 AN: 4804

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10580

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12308 AN: 67956

Other (OTH) AF: 0.227 AC: 478 AN: 2108

Alfa AF: 0.187 Hom.: 568

Bravo AF: 0.251

Asia WGS AF: 0.431 AC: 1500 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.1
DANN	Benign	0.49
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17076; hg19: chr2-179595117; COSMIC: COSV60101809; COSMIC: COSV60101809;