NM_001267550.2:c.53192T>C

Variant names:

• chr2-178607496-A-G
• rs72646809
• NM_001267550.2:c.53192T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.53192T>C​(p.Ile17731Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,256 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts 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. I17731I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.011 (155 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 8.89
• Publications: 14 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=0.00692603).
• BP6: Variant 2-178607496-A-G is Benign according to our data. Variant chr2-178607496-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1686/152104) while in subpopulation NFE AF = 0.0119 (810/67922). AF 95% confidence interval is 0.0112. There are 17 homozygotes in GnomAd4. There are 901 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

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.53192T>C	p.Ile17731Thr	missense	Exon 277 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.48269T>C	p.Ile16090Thr	missense	Exon 227 of 313	NP_001243779.1
	TTN	NM_133378.4		c.45488T>C	p.Ile15163Thr	missense	Exon 226 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.53192T>C	p.Ile17731Thr	missense	Exon 277 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.53036T>C	p.Ile17679Thr	missense	Exon 275 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.52916T>C	p.Ile17639Thr	missense	Exon 275 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1687 AN: 151986 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0471

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0137 AC: 3414 AN: 248660 AF XY: 0.0141

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00672

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0411

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0115 AC: 16781 AN: 1461152 Hom.: 155 Cov.: 32 AF XY: 0.0116 AC XY: 8398 AN XY: 726882

African (AFR) AF: 0.00185 AC: 62 AN: 33434

American (AMR) AF: 0.00729 AC: 326 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 788 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00904 AC: 780 AN: 86242

European-Finnish (FIN) AF: 0.0381 AC: 2036 AN: 53400

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5760

European-Non Finnish (NFE) AF: 0.0108 AC: 12016 AN: 1111478

Other (OTH) AF: 0.0116 AC: 698 AN: 60330

GnomAD4 genome AF: 0.0111 AC: 1686 AN: 152104 Hom.: 17 Cov.: 32 AF XY: 0.0121 AC XY: 901 AN XY: 74334

African (AFR) AF: 0.00250 AC: 104 AN: 41554

American (AMR) AF: 0.00465 AC: 71 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4830

European-Finnish (FIN) AF: 0.0471 AC: 500 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 810 AN: 67922

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0114 Hom.: 27

Bravo AF: 0.00797

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00237 AC: 9

ESP6500EA AF: 0.0143 AC: 118

ExAC AF: 0.0137 AC: 1652

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0134

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Benign	0.90
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0069	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.80
Sift	Benign	0.030	D
Polyphen		1.0	D
Vest4		0.38
MPC		0.52
ClinPred		0.039	T
GERP RS		6.0
Mutation Taster		=90/10	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: rs72646809; hg19: chr2-179472223; COSMIC: COSV99045884; COSMIC: COSV99045884;