rs56375087

Variant names:

• chr2-178531846-T-G
• rs56375087
• NM_001267550.2:c.104769A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.104769A>C​(p.Thr34923Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 1,613,842 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (165 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21
• Conservation: PhyloP100: -0.0280
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-178531846-T-G is Benign according to our data. Variant chr2-178531846-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47677.
• BP7: Synonymous conserved (PhyloP=-0.028 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1547/152276) while in subpopulation NFE AF = 0.00882 (600/68002). AF 95% confidence interval is 0.00824. There are 39 homozygotes in GnomAd4. There are 913 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.104769A>C	p.Thr34923Thr	synonymous	Exon 358 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.99846A>C	p.Thr33282Thr	synonymous	Exon 308 of 313	NP_001243779.1
	TTN	NM_133378.4		c.97065A>C	p.Thr32355Thr	synonymous	Exon 307 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.104769A>C	p.Thr34923Thr	synonymous	Exon 358 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.104613A>C	p.Thr34871Thr	synonymous	Exon 356 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.104493A>C	p.Thr34831Thr	synonymous	Exon 356 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1547 AN: 152158 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0762

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00882

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.0105 AC: 2606 AN: 248540 AF XY: 0.0104

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0706

Gnomad NFE exome AF: 0.00832

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00800 AC: 11694 AN: 1461566 Hom.: 165 Cov.: 40 AF XY: 0.00770 AC XY: 5596 AN XY: 727042

African (AFR) AF: 0.000836 AC: 28 AN: 33476

American (AMR) AF: 0.00119 AC: 53 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86248

European-Finnish (FIN) AF: 0.0662 AC: 3534 AN: 53388

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00676 AC: 7519 AN: 1111794

Other (OTH) AF: 0.00802 AC: 484 AN: 60370

GnomAD4 genome AF: 0.0102 AC: 1547 AN: 152276 Hom.: 39 Cov.: 32 AF XY: 0.0123 AC XY: 913 AN XY: 74458

African (AFR) AF: 0.00118 AC: 49 AN: 41578

American (AMR) AF: 0.00438 AC: 67 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0762 AC: 808 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00882 AC: 600 AN: 68002

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00768 Hom.: 2

Bravo AF: 0.00416

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00504

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.035
DANN	Benign	0.73
PhyloP100		-0.028
Mutation Taster		=97/3	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: rs56375087; hg19: chr2-179396573;