2-178652927-T-C

Variant names:

• chr2-178652927-T-C
• rs2742354
• NM_001267550.2:c.38880A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.38880A>G​(p.Pro12960Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,606,042 control chromosomes in the GnomAD database, including 735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P12960P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (71 hom., cov: 31)
  • Exomes 𝑓: 0.026 (664 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.81
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-178652927-T-C is Benign according to our data. Variant chr2-178652927-T-C is described in ClinVar as Benign. ClinVar VariationId is 413166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

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.38880A>G	p.Pro12960Pro	synonymous	Exon 200 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34523-386A>G		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31742-386A>G		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.38880A>G	p.Pro12960Pro	synonymous	Exon 200 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.38880A>G	p.Pro12960Pro	synonymous	Exon 200 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.38604A>G	p.Pro12868Pro	synonymous	Exon 198 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3523 AN: 151700 Hom.: 71 Cov.: 31

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0940

Gnomad SAS AF: 0.0312

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0327 AC: 7832 AN: 239346 AF XY: 0.0320

Gnomad AFR exome AF: 0.00487

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0476

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0314

GnomAD4 exome AF: 0.0259 AC: 37728 AN: 1454224 Hom.: 664 Cov.: 34 AF XY: 0.0261 AC XY: 18861 AN XY: 723214

African (AFR) AF: 0.00461 AC: 151 AN: 32744

American (AMR) AF: 0.0322 AC: 1379 AN: 42864

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 391 AN: 25658

East Asian (EAS) AF: 0.0913 AC: 3620 AN: 39642

South Asian (SAS) AF: 0.0281 AC: 2380 AN: 84720

European-Finnish (FIN) AF: 0.0490 AC: 2600 AN: 53050

Middle Eastern (MID) AF: 0.0146 AC: 83 AN: 5692

European-Non Finnish (NFE) AF: 0.0230 AC: 25540 AN: 1109930

Other (OTH) AF: 0.0264 AC: 1584 AN: 59924

GnomAD4 genome AF: 0.0232 AC: 3523 AN: 151818 Hom.: 71 Cov.: 31 AF XY: 0.0239 AC XY: 1772 AN XY: 74188

African (AFR) AF: 0.00495 AC: 205 AN: 41410

American (AMR) AF: 0.0252 AC: 384 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3468

East Asian (EAS) AF: 0.0942 AC: 482 AN: 5116

South Asian (SAS) AF: 0.0312 AC: 150 AN: 4802

European-Finnish (FIN) AF: 0.0450 AC: 475 AN: 10546

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.0247 AC: 1679 AN: 67926

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0175 Hom.: 9

Bravo AF: 0.0209

Asia WGS AF: 0.0490 AC: 168 AN: 3476

EpiCase AF: 0.0226

EpiControl AF: 0.0241

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (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	-0.68
CADD	Benign	0.0040
DANN	Benign	0.74
PhyloP100		-3.8
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: rs2742354; hg19: chr2-179517654;