NM_001267550.2:c.4715G>A

Variant names:

• chr2-178777248-C-T
• rs12476289
• NM_001267550.2:c.4715G>A

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.4715G>A​(p.Arg1572Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0524 in 1,613,960 control chromosomes in the GnomAD database, including 3,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1572R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.050 (362 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3402 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.791
• Publications: 38 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]

LOC101927055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012369156).
• BP6: Variant 2-178777248-C-T is Benign according to our data. Variant chr2-178777248-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 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.4715G>A	p.Arg1572Gln	missense	Exon 27 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.4715G>A	p.Arg1572Gln	missense	Exon 27 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.4715G>A	p.Arg1572Gln	missense	Exon 27 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.4715G>A	p.Arg1572Gln	missense	Exon 27 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.4715G>A	p.Arg1572Gln	missense	Exon 27 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.4439G>A	p.Arg1480Gln	missense	Exon 25 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7566 AN: 152090 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0787 AC: 19735 AN: 250872 AF XY: 0.0694

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0443

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0527 AC: 76974 AN: 1461752 Hom.: 3402 Cov.: 34 AF XY: 0.0508 AC XY: 36966 AN XY: 727178

African (AFR) AF: 0.00941 AC: 315 AN: 33474

American (AMR) AF: 0.228 AC: 10174 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1238 AN: 26132

East Asian (EAS) AF: 0.188 AC: 7452 AN: 39670

South Asian (SAS) AF: 0.0197 AC: 1695 AN: 86250

European-Finnish (FIN) AF: 0.0546 AC: 2914 AN: 53402

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5768

European-Non Finnish (NFE) AF: 0.0450 AC: 49994 AN: 1111948

Other (OTH) AF: 0.0513 AC: 3098 AN: 60390

GnomAD4 genome AF: 0.0497 AC: 7569 AN: 152208 Hom.: 362 Cov.: 32 AF XY: 0.0514 AC XY: 3821 AN XY: 74398

African (AFR) AF: 0.0116 AC: 480 AN: 41542

American (AMR) AF: 0.138 AC: 2110 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3470

East Asian (EAS) AF: 0.183 AC: 951 AN: 5184

South Asian (SAS) AF: 0.0212 AC: 102 AN: 4816

European-Finnish (FIN) AF: 0.0513 AC: 544 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0451 AC: 3069 AN: 68000

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0494 Hom.: 1242

Bravo AF: 0.0607

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0430 AC: 370

ExAC AF: 0.0711 AC: 8629

Asia WGS AF: 0.0730 AC: 254 AN: 3478

EpiCase AF: 0.0404

EpiControl AF: 0.0427

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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	0.019
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.79
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.064
Sift	Benign	0.60	T
Sift4G	Benign	0.27	T
Polyphen		0.75	P
Vest4		0.089
MPC		0.11
ClinPred		0.014	T
GERP RS		5.0
Mutation Taster		=94/6	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: rs12476289; hg19: chr2-179641975; COSMIC: COSV59946654; COSMIC: COSV59946654;