2-178546088-G-A

Variant names:

• chr2-178546088-G-A
• rs140663434
• NM_001267550.2:c.95148C>T

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.95148C>T​(p.Thr31716Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,610,798 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (46 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -2.71
• 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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-178546088-G-A is Benign according to our data. Variant chr2-178546088-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0018 (274/152312) while in subpopulation SAS AF = 0.024 (116/4824). AF 95% confidence interval is 0.0205. There are 5 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.95148C>T	p.Thr31716Thr	synonymous	Exon 343 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.90225C>T	p.Thr30075Thr	synonymous	Exon 293 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87444C>T	p.Thr29148Thr	synonymous	Exon 292 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.95148C>T	p.Thr31716Thr	synonymous	Exon 343 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.94992C>T	p.Thr31664Thr	synonymous	Exon 341 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94872C>T	p.Thr31624Thr	synonymous	Exon 341 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152194 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00360 AC: 885 AN: 245816 AF XY: 0.00457

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000727

Gnomad ASJ exome AF: 0.000925

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00219 AC: 3200 AN: 1458486 Hom.: 46 Cov.: 33 AF XY: 0.00280 AC XY: 2028 AN XY: 725226

African (AFR) AF: 0.000419 AC: 14 AN: 33406

American (AMR) AF: 0.000650 AC: 29 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.000811 AC: 21 AN: 25906

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39650

South Asian (SAS) AF: 0.0208 AC: 1787 AN: 85974

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53228

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5748

European-Non Finnish (NFE) AF: 0.00102 AC: 1133 AN: 1109692

Other (OTH) AF: 0.00295 AC: 178 AN: 60252

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152312 Hom.: 5 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74476

African (AFR) AF: 0.000241 AC: 10 AN: 41574

American (AMR) AF: 0.00183 AC: 28 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68024

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00105

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.0080
DANN	Benign	0.76
PhyloP100		-2.7
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

Other links and lift over

dbSNP: rs140663434; hg19: chr2-179410815;