NM_001267550.2:c.102833G>T

Variant names:

• chr2-178533782-C-A
• rs3731752
• NM_001267550.2:c.102833G>T

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.102833G>T​(p.Gly34278Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,613,856 control chromosomes in the GnomAD database, including 1,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (212 hom., cov: 32)
  • Exomes 𝑓: 0.028 (1231 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 7.88
• Publications: 23 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=0.0017593205).
• BP6: Variant 2-178533782-C-A is Benign according to our data. Variant chr2-178533782-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 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.102833G>T	p.Gly34278Val	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.97910G>T	p.Gly32637Val	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.95129G>T	p.Gly31710Val	missense	Exon 307 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.102833G>T	p.Gly34278Val	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.102677G>T	p.Gly34226Val	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.102557G>T	p.Gly34186Val	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6224 AN: 152086 Hom.: 212 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0452

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0540

GnomAD2 exomes AF: 0.0393 AC: 9800 AN: 249144 AF XY: 0.0392

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.00348

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0281 AC: 41023 AN: 1461652 Hom.: 1231 Cov.: 40 AF XY: 0.0284 AC XY: 20686 AN XY: 727108

African (AFR) AF: 0.0708 AC: 2371 AN: 33476

American (AMR) AF: 0.0330 AC: 1475 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 1110 AN: 26136

East Asian (EAS) AF: 0.179 AC: 7095 AN: 39696

South Asian (SAS) AF: 0.0470 AC: 4053 AN: 86256

European-Finnish (FIN) AF: 0.00331 AC: 177 AN: 53394

Middle Eastern (MID) AF: 0.0784 AC: 452 AN: 5768

European-Non Finnish (NFE) AF: 0.0199 AC: 22125 AN: 1111834

Other (OTH) AF: 0.0359 AC: 2165 AN: 60372

GnomAD4 genome AF: 0.0410 AC: 6236 AN: 152204 Hom.: 212 Cov.: 32 AF XY: 0.0407 AC XY: 3025 AN XY: 74400

African (AFR) AF: 0.0705 AC: 2925 AN: 41516

American (AMR) AF: 0.0388 AC: 593 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3472

East Asian (EAS) AF: 0.164 AC: 849 AN: 5162

South Asian (SAS) AF: 0.0454 AC: 219 AN: 4820

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1348 AN: 68012

Other (OTH) AF: 0.0544 AC: 115 AN: 2114

Alfa AF: 0.0301 Hom.: 544

Bravo AF: 0.0449

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.0644 AC: 245

ESP6500EA AF: 0.0198 AC: 163

ExAC AF: 0.0392 AC: 4732

Asia WGS AF: 0.0950 AC: 328 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.90
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.28	N
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.48
Sift	Benign	0.045	D
Polyphen		1.0	D
Vest4		0.45
MPC		0.51
ClinPred		0.041	T
GERP RS		5.6
Mutation Taster		=89/11	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: rs3731752; hg19: chr2-179398509; COSMIC: COSV60296493; COSMIC: COSV60296493;