2-178713976-C-T

Variant names:

• chr2-178713976-C-T
• rs142812510
• NM_001267550.2:c.26682G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.26682G>A​(p.Pro8894Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,613,606 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P8894P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (33 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -0.207
• Publications: 0 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=-0.74).
• BP6: Variant 2-178713976-C-T is Benign according to our data. Variant chr2-178713976-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.207 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00283 (431/152270) while in subpopulation SAS AF = 0.0149 (72/4832). AF 95% confidence interval is 0.0121. There are 4 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.26682G>A	p.Pro8894Pro	synonymous	Exon 92 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25731G>A	p.Pro8577Pro	synonymous	Exon 90 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.22950G>A	p.Pro7650Pro	synonymous	Exon 89 of 312	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.26682G>A	p.Pro8894Pro	synonymous	Exon 92 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26682G>A	p.Pro8894Pro	synonymous	Exon 92 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26406G>A	p.Pro8802Pro	synonymous	Exon 90 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152152 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00470 AC: 1170 AN: 248764 AF XY: 0.00565

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00865

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00348

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00380 AC: 5550 AN: 1461336 Hom.: 33 Cov.: 31 AF XY: 0.00432 AC XY: 3141 AN XY: 726930

African (AFR) AF: 0.000478 AC: 16 AN: 33458

American (AMR) AF: 0.00121 AC: 54 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 196 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0172 AC: 1485 AN: 86226

European-Finnish (FIN) AF: 0.00399 AC: 213 AN: 53378

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5764

European-Non Finnish (NFE) AF: 0.00292 AC: 3249 AN: 1111658

Other (OTH) AF: 0.00436 AC: 263 AN: 60352

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152270 Hom.: 4 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74454

African (AFR) AF: 0.000433 AC: 18 AN: 41564

American (AMR) AF: 0.00170 AC: 26 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4832

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00346 AC: 235 AN: 68002

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00209

Asia WGS AF: 0.00491 AC: 17 AN: 3476

EpiCase AF: 0.00404

EpiControl AF: 0.00469

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		-0.21
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: rs142812510; hg19: chr2-179578703; COSMIC: COSV104642040;