rs2742332

Variant names:

• chr2-178709657-C-T
• rs2742332
• NM_001267550.2:c.28662G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.28662G>A​(p.Arg9554Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,613,856 control chromosomes in the GnomAD database, including 1,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R9554R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (250 hom., cov: 33)
  • Exomes 𝑓: 0.032 (1450 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 3.35
• Publications: 10 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=-0.31).
• BP6: Variant 2-178709657-C-T is Benign according to our data. Variant chr2-178709657-C-T is described in ClinVar as Benign. ClinVar VariationId is 46812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 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.28662G>A	p.Arg9554Arg	synonymous	Exon 99 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.27711G>A	p.Arg9237Arg	synonymous	Exon 97 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.24930G>A	p.Arg8310Arg	synonymous	Exon 96 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.28662G>A	p.Arg9554Arg	synonymous	Exon 99 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.28662G>A	p.Arg9554Arg	synonymous	Exon 99 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.28386G>A	p.Arg9462Arg	synonymous	Exon 97 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6852 AN: 152142 Hom.: 251 Cov.: 33

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0454

GnomAD2 exomes AF: 0.0476 AC: 11850 AN: 249176 AF XY: 0.0444

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.0497

Gnomad NFE exome AF: 0.0260

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0317 AC: 46386 AN: 1461596 Hom.: 1450 Cov.: 31 AF XY: 0.0315 AC XY: 22871 AN XY: 727086

African (AFR) AF: 0.0620 AC: 2075 AN: 33470

American (AMR) AF: 0.0433 AC: 1937 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 852 AN: 26130

East Asian (EAS) AF: 0.191 AC: 7579 AN: 39692

South Asian (SAS) AF: 0.0306 AC: 2641 AN: 86256

European-Finnish (FIN) AF: 0.0514 AC: 2746 AN: 53400

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5768

European-Non Finnish (NFE) AF: 0.0236 AC: 26288 AN: 1111788

Other (OTH) AF: 0.0358 AC: 2164 AN: 60374

GnomAD4 genome AF: 0.0450 AC: 6848 AN: 152260 Hom.: 250 Cov.: 33 AF XY: 0.0457 AC XY: 3398 AN XY: 74428

African (AFR) AF: 0.0634 AC: 2636 AN: 41548

American (AMR) AF: 0.0363 AC: 556 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3472

East Asian (EAS) AF: 0.191 AC: 989 AN: 5176

South Asian (SAS) AF: 0.0362 AC: 175 AN: 4828

European-Finnish (FIN) AF: 0.0475 AC: 504 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1735 AN: 68004

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0340 Hom.: 327

Bravo AF: 0.0469

Asia WGS AF: 0.0850 AC: 293 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0251

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	10
DANN	Benign	0.58
PhyloP100		3.3
Mutation Taster		=22/78	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: rs2742332; hg19: chr2-179574384; COSMIC: COSV59946384;