NM_001267550.2:c.29178C>A

Variant names:

• chr2-178706696-G-T
• rs72650003
• NM_001267550.2:c.29178C>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.29178C>A​(p.Ile9726Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,612,982 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (45 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.52
• 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-178706696-G-T is Benign according to our data. Variant chr2-178706696-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00366 (558/152282) while in subpopulation EAS AF = 0.0399 (207/5188). AF 95% confidence interval is 0.0355. There are 6 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.29178C>A	p.Ile9726Ile	synonymous	Exon 102 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.28227C>A	p.Ile9409Ile	synonymous	Exon 100 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.25446C>A	p.Ile8482Ile	synonymous	Exon 99 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.29178C>A	p.Ile9726Ile	synonymous	Exon 102 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.29178C>A	p.Ile9726Ile	synonymous	Exon 102 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.28902C>A	p.Ile9634Ile	synonymous	Exon 100 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152164 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00587 AC: 1460 AN: 248838 AF XY: 0.00588

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0422

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00409 AC: 5968 AN: 1460700 Hom.: 45 Cov.: 31 AF XY: 0.00402 AC XY: 2922 AN XY: 726418

African (AFR) AF: 0.000419 AC: 14 AN: 33444

American (AMR) AF: 0.000425 AC: 19 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26112

East Asian (EAS) AF: 0.0363 AC: 1442 AN: 39682

South Asian (SAS) AF: 0.00303 AC: 261 AN: 86150

European-Finnish (FIN) AF: 0.0111 AC: 593 AN: 53388

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5760

European-Non Finnish (NFE) AF: 0.00302 AC: 3361 AN: 1111108

Other (OTH) AF: 0.00437 AC: 264 AN: 60348

GnomAD4 genome AF: 0.00366 AC: 558 AN: 152282 Hom.: 6 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74470

African (AFR) AF: 0.000578 AC: 24 AN: 41558

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0399 AC: 207 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00895 AC: 95 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00296 AC: 201 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00207 Hom.: 2

Bravo AF: 0.00344

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	-0.36
CADD	Benign	4.3
DANN	Benign	0.73
PhyloP100		1.5
Mutation Taster		=80/20	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: rs72650003; hg19: chr2-179571423;