rs3829746

Variant names:

• chr2-178562809-T-C
• rs3829746
• NM_001267550.2:c.83323A>G
• TTN p.Ile27775Val

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.83323A>G​(p.Ile27775Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,612,474 control chromosomes in the GnomAD database, including 74,712 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27775T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.36 (11855 hom., cov: 33)
  • Exomes 𝑓: 0.27 (62857 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.477
• Publications: 46 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.253756E-6).
• BP6: Variant 2-178562809-T-C is Benign according to our data. Variant chr2-178562809-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 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.83323A>G	p.Ile27775Val	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.78400A>G	p.Ile26134Val	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.75619A>G	p.Ile25207Val	missense	Exon 275 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.83323A>G	p.Ile27775Val	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.83167A>G	p.Ile27723Val	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.83047A>G	p.Ile27683Val	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54920 AN: 151850 Hom.: 11806 Cov.: 33

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.352 AC: 86795 AN: 246406 AF XY: 0.349

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.269 AC: 392178 AN: 1460506 Hom.: 62857 Cov.: 40 AF XY: 0.274 AC XY: 198713 AN XY: 726470

African (AFR) AF: 0.556 AC: 18602 AN: 33458

American (AMR) AF: 0.425 AC: 18935 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7303 AN: 26116

East Asian (EAS) AF: 0.694 AC: 27427 AN: 39530

South Asian (SAS) AF: 0.504 AC: 43445 AN: 86222

European-Finnish (FIN) AF: 0.277 AC: 14763 AN: 53294

Middle Eastern (MID) AF: 0.307 AC: 1771 AN: 5768

European-Non Finnish (NFE) AF: 0.217 AC: 241659 AN: 1111286

Other (OTH) AF: 0.303 AC: 18273 AN: 60288

GnomAD4 genome AF: 0.362 AC: 55030 AN: 151968 Hom.: 11855 Cov.: 33 AF XY: 0.372 AC XY: 27638 AN XY: 74304

African (AFR) AF: 0.542 AC: 22461 AN: 41434

American (AMR) AF: 0.384 AC: 5864 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3468

East Asian (EAS) AF: 0.701 AC: 3595 AN: 5132

South Asian (SAS) AF: 0.514 AC: 2479 AN: 4822

European-Finnish (FIN) AF: 0.285 AC: 3022 AN: 10586

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15318 AN: 67952

Other (OTH) AF: 0.336 AC: 711 AN: 2116

Alfa AF: 0.280 Hom.: 23953

Bravo AF: 0.376

Asia WGS AF: 0.618 AC: 2146 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.9
DANN	Benign	0.86
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0000042	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.54	N
PhyloP100		0.48
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3829746;

hg19: chr2-179427536;

COSMIC: COSV60156917;

COSMIC: COSV60156917;