NM_001267550.2:c.47545C>A

Variant names:

• chr2-178617806-G-T
• rs146181477
• NM_001267550.2:c.47545C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.47545C>A​(p.Pro15849Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,612,350 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15849R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (48 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: 3.84
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043167174).
• BP6: Variant 2-178617806-G-T is Benign according to our data. Variant chr2-178617806-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47013.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00178 (270/151972) while in subpopulation SAS AF = 0.0243 (117/4824). AF 95% confidence interval is 0.0207. There are 5 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.47545C>A	p.Pro15849Thr	missense	Exon 253 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.42622C>A	p.Pro14208Thr	missense	Exon 203 of 313	NP_001243779.1
	TTN	NM_133378.4		c.39841C>A	p.Pro13281Thr	missense	Exon 202 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.47545C>A	p.Pro15849Thr	missense	Exon 253 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.47389C>A	p.Pro15797Thr	missense	Exon 251 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.47269C>A	p.Pro15757Thr	missense	Exon 251 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 151854 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00373 AC: 924 AN: 247722 AF XY: 0.00476

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00222 AC: 3249 AN: 1460378 Hom.: 48 Cov.: 32 AF XY: 0.00285 AC XY: 2067 AN XY: 726498

African (AFR) AF: 0.000330 AC: 11 AN: 33376

American (AMR) AF: 0.000694 AC: 31 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.000843 AC: 22 AN: 26088

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39554

South Asian (SAS) AF: 0.0211 AC: 1818 AN: 86200

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53386

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5754

European-Non Finnish (NFE) AF: 0.00105 AC: 1172 AN: 1111082

Other (OTH) AF: 0.00272 AC: 164 AN: 60284

GnomAD4 genome AF: 0.00178 AC: 270 AN: 151972 Hom.: 5 Cov.: 33 AF XY: 0.00205 AC XY: 152 AN XY: 74286

African (AFR) AF: 0.000169 AC: 7 AN: 41512

American (AMR) AF: 0.00171 AC: 26 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.0243 AC: 117 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67888

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00164 Hom.: 1

Bravo AF: 0.00105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00193 AC: 16

ExAC AF: 0.00430 AC: 519

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	5	not provided (6)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.89
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.15
Sift	Benign	0.51	T
Polyphen		0.26	B
Vest4		0.33
MVP		0.23
MPC		0.11
ClinPred		0.022	T
GERP RS		5.5
Mutation Taster		=99/1	polymorphism

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: rs146181477; hg19: chr2-179482533;