2-178565333-G-T

Variant names:

• chr2-178565333-G-T
• rs3813247
• NM_001267550.2:c.80799C>A

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.80799C>A​(p.Thr26933Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,613,562 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (51 hom., cov: 33)
  • Exomes 𝑓: 0.023 (470 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.00400
• Publications: 7 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=-0.75).
• BP6: Variant 2-178565333-G-T is Benign according to our data. Variant chr2-178565333-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.004 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0552 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.80799C>A	p.Thr26933Thr	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.75876C>A	p.Thr25292Thr	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.73095C>A	p.Thr24365Thr	synonymous	Exon 275 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.80799C>A	p.Thr26933Thr	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.80643C>A	p.Thr26881Thr	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.80523C>A	p.Thr26841Thr	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3067 AN: 152044 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0606

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0258 AC: 6421 AN: 248462 AF XY: 0.0244

Gnomad AFR exome AF: 0.00485

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0608

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0230 AC: 33649 AN: 1461400 Hom.: 470 Cov.: 37 AF XY: 0.0226 AC XY: 16451 AN XY: 726990

African (AFR) AF: 0.00404 AC: 135 AN: 33454

American (AMR) AF: 0.0318 AC: 1423 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 375 AN: 26124

East Asian (EAS) AF: 0.0625 AC: 2481 AN: 39678

South Asian (SAS) AF: 0.00667 AC: 575 AN: 86238

European-Finnish (FIN) AF: 0.0483 AC: 2577 AN: 53402

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5758

European-Non Finnish (NFE) AF: 0.0222 AC: 24718 AN: 1111672

Other (OTH) AF: 0.0217 AC: 1308 AN: 60356

GnomAD4 genome AF: 0.0201 AC: 3064 AN: 152162 Hom.: 51 Cov.: 33 AF XY: 0.0206 AC XY: 1532 AN XY: 74386

African (AFR) AF: 0.00448 AC: 186 AN: 41526

American (AMR) AF: 0.0215 AC: 329 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.0607 AC: 313 AN: 5154

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4820

European-Finnish (FIN) AF: 0.0448 AC: 475 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1586 AN: 68000

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0224 Hom.: 126

Bravo AF: 0.0185

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0217

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	not provided (3)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.029
DANN	Benign	0.71
PhyloP100		0.0040
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs3813247; hg19: chr2-179430060; COSMIC: COSV60085109;