rs1883084

Variant names:

• chr2-178740015-G-A
• rs1883084
• NM_001267550.2:c.13218C>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.13218C>T​(p.Ala4406Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,613,746 control chromosomes in the GnomAD database, including 3,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (382 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3468 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.844
• Publications: 11 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=-0.86).
• BP6: Variant 2-178740015-G-A is Benign according to our data. Variant chr2-178740015-G-A is described in ClinVar as Benign. ClinVar VariationId is 47836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.844 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 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.13218C>T	p.Ala4406Ala	synonymous	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.12267C>T	p.Ala4089Ala	synonymous	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.12705C>T	p.Ala4235Ala	synonymous	Exon 46 of 192	NP_597681.4	A0A0A0MRA3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.13218C>T	p.Ala4406Ala	synonymous	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.13218C>T	p.Ala4406Ala	synonymous	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.12942C>T	p.Ala4314Ala	synonymous	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 7708 AN: 152038 Hom.: 381 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0486

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0231

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0799 AC: 19858 AN: 248418 AF XY: 0.0704

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0674

GnomAD4 exome AF: 0.0531 AC: 77589 AN: 1461590 Hom.: 3468 Cov.: 31 AF XY: 0.0513 AC XY: 37299 AN XY: 727066

African (AFR) AF: 0.0126 AC: 423 AN: 33476

American (AMR) AF: 0.229 AC: 10235 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1238 AN: 26130

East Asian (EAS) AF: 0.189 AC: 7498 AN: 39672

South Asian (SAS) AF: 0.0201 AC: 1733 AN: 86258

European-Finnish (FIN) AF: 0.0546 AC: 2914 AN: 53388

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5766

European-Non Finnish (NFE) AF: 0.0453 AC: 50322 AN: 1111820

Other (OTH) AF: 0.0519 AC: 3133 AN: 60364

GnomAD4 genome AF: 0.0507 AC: 7711 AN: 152156 Hom.: 382 Cov.: 32 AF XY: 0.0523 AC XY: 3891 AN XY: 74396

African (AFR) AF: 0.0140 AC: 583 AN: 41532

American (AMR) AF: 0.138 AC: 2105 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 168 AN: 3460

East Asian (EAS) AF: 0.189 AC: 974 AN: 5164

South Asian (SAS) AF: 0.0225 AC: 108 AN: 4808

European-Finnish (FIN) AF: 0.0512 AC: 543 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0454 AC: 3086 AN: 67994

Other (OTH) AF: 0.0455 AC: 96 AN: 2112

Alfa AF: 0.0450 Hom.: 100

Bravo AF: 0.0616

Asia WGS AF: 0.0770 AC: 265 AN: 3476

EpiCase AF: 0.0407

EpiControl AF: 0.0431

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.36
DANN	Benign	0.84
PhyloP100		-0.84
Mutation Taster		=96/4	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: rs1883084; hg19: chr2-179604742; COSMIC: COSV59946529; COSMIC: COSV59946529;