rs72648950

Variant names:

• chr2-178729135-G-A
• rs72648950
• NM_001267550.2:c.18903C>T

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.18903C>T​(p.Thr6301Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,597,376 control chromosomes in the GnomAD database, including 909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (163 hom., cov: 33)
  • Exomes 𝑓: 0.012 (746 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 2.86
• 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=-0.54).
• BP6: Variant 2-178729135-G-A is Benign according to our data. Variant chr2-178729135-G-A is described in ClinVar as Benign. ClinVar VariationId is 46649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.122 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.18903C>T	p.Thr6301Thr	synonymous	Exon 65 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.17952C>T	p.Thr5984Thr	synonymous	Exon 63 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15171C>T	p.Thr5057Thr	synonymous	Exon 62 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.18903C>T	p.Thr6301Thr	synonymous	Exon 65 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.18903C>T	p.Thr6301Thr	synonymous	Exon 65 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18627C>T	p.Thr6209Thr	synonymous	Exon 63 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2959 AN: 151966 Hom.: 160 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00634

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0328 AC: 7588 AN: 231630 AF XY: 0.0267

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.00136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0296

Gnomad NFE exome AF: 0.00621

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0119 AC: 17149 AN: 1445292 Hom.: 746 Cov.: 32 AF XY: 0.0110 AC XY: 7901 AN XY: 717326

African (AFR) AF: 0.00265 AC: 87 AN: 32772

American (AMR) AF: 0.174 AC: 7411 AN: 42484

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 45 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 39386

South Asian (SAS) AF: 0.0112 AC: 929 AN: 83264

European-Finnish (FIN) AF: 0.0302 AC: 1595 AN: 52752

Middle Eastern (MID) AF: 0.00548 AC: 31 AN: 5658

European-Non Finnish (NFE) AF: 0.00581 AC: 6416 AN: 1104128

Other (OTH) AF: 0.0106 AC: 635 AN: 59646

GnomAD4 genome AF: 0.0195 AC: 2967 AN: 152084 Hom.: 163 Cov.: 33 AF XY: 0.0229 AC XY: 1702 AN XY: 74318

African (AFR) AF: 0.00443 AC: 184 AN: 41526

American (AMR) AF: 0.126 AC: 1925 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4820

European-Finnish (FIN) AF: 0.0291 AC: 308 AN: 10582

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00634 AC: 431 AN: 67966

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00896 Hom.: 17

Bravo AF: 0.0260

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	not provided (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	-0.54
CADD	Benign	7.3
DANN	Benign	0.55
PhyloP100		2.9
Mutation Taster		=95/5	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: rs72648950; hg19: chr2-179593862;