rs72646827

Variant names:

• chr2-178599264-C-T
• rs72646827
• NM_001267550.2:c.56529G>A

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.56529G>A​(p.Thr18843Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,581,630 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (1 hom., cov: 32)
  • Exomes 𝑓: 0.011 (101 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.0380
• Publications: 3 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=-0.55).
• BP6: Variant 2-178599264-C-T is Benign according to our data. Variant chr2-178599264-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.038 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00675 (1026/152090) while in subpopulation NFE AF = 0.0114 (772/67984). AF 95% confidence interval is 0.0107. There are 1 homozygotes in GnomAd4. There are 448 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 101 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.56529G>A	p.Thr18843Thr	synonymous	Exon 290 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.51606G>A	p.Thr17202Thr	synonymous	Exon 240 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.48825G>A	p.Thr16275Thr	synonymous	Exon 239 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.56529G>A	p.Thr18843Thr	synonymous	Exon 290 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.56373G>A	p.Thr18791Thr	synonymous	Exon 288 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.56253G>A	p.Thr18751Thr	synonymous	Exon 288 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 1028 AN: 151972 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00800 AC: 1752 AN: 218928 AF XY: 0.00796

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00849

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00472

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00519

GnomAD4 exome AF: 0.0108 AC: 15476 AN: 1429540 Hom.: 101 Cov.: 32 AF XY: 0.0105 AC XY: 7483 AN XY: 709576

African (AFR) AF: 0.00145 AC: 46 AN: 31762

American (AMR) AF: 0.00777 AC: 290 AN: 37306

Ashkenazi Jewish (ASJ) AF: 0.00213 AC: 51 AN: 23998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00441 AC: 348 AN: 78994

European-Finnish (FIN) AF: 0.00587 AC: 308 AN: 52460

Middle Eastern (MID) AF: 0.00125 AC: 7 AN: 5602

European-Non Finnish (NFE) AF: 0.0127 AC: 13974 AN: 1101008

Other (OTH) AF: 0.00766 AC: 452 AN: 59022

GnomAD4 genome AF: 0.00675 AC: 1026 AN: 152090 Hom.: 1 Cov.: 32 AF XY: 0.00603 AC XY: 448 AN XY: 74324

African (AFR) AF: 0.00255 AC: 106 AN: 41522

American (AMR) AF: 0.00400 AC: 61 AN: 15268

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

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5128

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4816

European-Finnish (FIN) AF: 0.00378 AC: 40 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0114 AC: 772 AN: 67984

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00841 Hom.: 3

Bravo AF: 0.00703

Asia WGS AF: 0.00115 AC: 4 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	-0.55
CADD	Benign	1.3
DANN	Benign	0.75
PhyloP100		0.038
Mutation Taster		=100/0	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: rs72646827; hg19: chr2-179463991;