rs56345408

Variant names:

• chr2-178563392-C-T
• rs56345408
• NM_001267550.2:c.82740G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.82740G>A​(p.Thr27580Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,613,440 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (89 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: -0.0250
• 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]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-178563392-C-T is Benign according to our data. Variant chr2-178563392-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00608 (924/152028) while in subpopulation SAS AF = 0.0239 (115/4812). AF 95% confidence interval is 0.0204. There are 8 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.82740G>A	p.Thr27580Thr	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.77817G>A	p.Thr25939Thr	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.75036G>A	p.Thr25012Thr	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.82740G>A	p.Thr27580Thr	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.82584G>A	p.Thr27528Thr	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.82464G>A	p.Thr27488Thr	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 921 AN: 151910 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00802

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00812 AC: 2015 AN: 248068 AF XY: 0.00910

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00785

Gnomad OTH exome AF: 0.00862

GnomAD4 exome AF: 0.00730 AC: 10666 AN: 1461412 Hom.: 89 Cov.: 37 AF XY: 0.00783 AC XY: 5690 AN XY: 727002

African (AFR) AF: 0.000867 AC: 29 AN: 33466

American (AMR) AF: 0.00228 AC: 102 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26128

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39618

South Asian (SAS) AF: 0.0208 AC: 1793 AN: 86256

European-Finnish (FIN) AF: 0.0151 AC: 805 AN: 53396

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5766

European-Non Finnish (NFE) AF: 0.00670 AC: 7445 AN: 1111720

Other (OTH) AF: 0.00666 AC: 402 AN: 60358

GnomAD4 genome AF: 0.00608 AC: 924 AN: 152028 Hom.: 8 Cov.: 33 AF XY: 0.00652 AC XY: 484 AN XY: 74274

African (AFR) AF: 0.00128 AC: 53 AN: 41508

American (AMR) AF: 0.00263 AC: 40 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.0239 AC: 115 AN: 4812

European-Finnish (FIN) AF: 0.0139 AC: 147 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00802 AC: 545 AN: 67972

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00561 Hom.: 1

Bravo AF: 0.00418

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00788

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.48
DANN	Benign	0.80
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	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: rs56345408; hg19: chr2-179428119;