2-178662748-C-T

Variant names:

• chr2-178662748-C-T
• rs535294541
• NM_001267550.2:c.36855G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001267550.2(TTN):​c.36855G>A​(p.Pro12285Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (59 hom., cov: 18)
  • Exomes 𝑓: 0.010 (109 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.05
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-178662748-C-T is Benign according to our data. Variant chr2-178662748-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.05 with no splicing effect.

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.36855G>A	p.Pro12285Pro	synonymous	Exon 175 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34354+218G>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31573+218G>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.36855G>A	p.Pro12285Pro	synonymous	Exon 175 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36855G>A	p.Pro12285Pro	synonymous	Exon 175 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36579G>A	p.Pro12193Pro	synonymous	Exon 173 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 2884 AN: 130048 Hom.: 59 Cov.: 18

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.00607

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.00379

Gnomad EAS AF: 0.00732

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0167 AC: 955 AN: 57318 AF XY: 0.0163

Gnomad AFR exome AF: 0.0633

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.00608

Gnomad FIN exome AF: 0.00809

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0176

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 12724 AN: 1217584 Hom.: 109 Cov.: 17 AF XY: 0.0106 AC XY: 6438 AN XY: 608696

African (AFR) AF: 0.0623 AC: 1730 AN: 27754

American (AMR) AF: 0.0118 AC: 430 AN: 36494

Ashkenazi Jewish (ASJ) AF: 0.00474 AC: 103 AN: 21740

East Asian (EAS) AF: 0.00341 AC: 127 AN: 37286

South Asian (SAS) AF: 0.0178 AC: 1320 AN: 74292

European-Finnish (FIN) AF: 0.0129 AC: 476 AN: 37028

Middle Eastern (MID) AF: 0.0221 AC: 78 AN: 3530

European-Non Finnish (NFE) AF: 0.00827 AC: 7675 AN: 927708

Other (OTH) AF: 0.0152 AC: 785 AN: 51752

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0222 AC: 2894 AN: 130134 Hom.: 59 Cov.: 18 AF XY: 0.0223 AC XY: 1387 AN XY: 62206

African (AFR) AF: 0.0573 AC: 1939 AN: 33856

American (AMR) AF: 0.0200 AC: 254 AN: 12674

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 12 AN: 3166

East Asian (EAS) AF: 0.00712 AC: 31 AN: 4356

South Asian (SAS) AF: 0.0131 AC: 47 AN: 3600

European-Finnish (FIN) AF: 0.0127 AC: 106 AN: 8316

Middle Eastern (MID) AF: 0.0257 AC: 7 AN: 272

European-Non Finnish (NFE) AF: 0.00735 AC: 451 AN: 61368

Other (OTH) AF: 0.0247 AC: 42 AN: 1702

Alfa AF: 0.0168 Hom.: 4

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs535294541; hg19: chr2-179527475;