rs201035511

Variant names:

• chr2-178602584-G-A
• rs201035511
• NM_001267550.2:c.54818C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178602584-G-A
• chr2-178602584-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001267550.2(TTN):​c.54818C>T​(p.Pro18273Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00063 in 1,503,086 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P18273P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:9
• Conservation: PhyloP100: 9.94
• Publications: 6 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19510445).
• BP6: Variant 2-178602584-G-A is Benign according to our data. Variant chr2-178602584-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47097.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.54818C>T	p.Pro18273Leu	missense	Exon 283 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.49895C>T	p.Pro16632Leu	missense	Exon 233 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.47114C>T	p.Pro15705Leu	missense	Exon 232 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.54818C>T	p.Pro18273Leu	missense	Exon 283 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.54662C>T	p.Pro18221Leu	missense	Exon 281 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.54542C>T	p.Pro18181Leu	missense	Exon 281 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000481 AC: 73 AN: 151728 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000854

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000411 AC: 51 AN: 124118 AF XY: 0.000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.000788

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000790

Gnomad OTH exome AF: 0.000314

GnomAD4 exome AF: 0.000647 AC: 874 AN: 1351240 Hom.: 2 Cov.: 32 AF XY: 0.000648 AC XY: 430 AN XY: 663332

African (AFR) AF: 0.0000684 AC: 2 AN: 29252

American (AMR) AF: 0.000307 AC: 7 AN: 22782

Ashkenazi Jewish (ASJ) AF: 0.000817 AC: 18 AN: 22026

East Asian (EAS) AF: 0.00 AC: 0 AN: 36202

South Asian (SAS) AF: 0.00 AC: 0 AN: 70138

European-Finnish (FIN) AF: 0.000103 AC: 5 AN: 48724

Middle Eastern (MID) AF: 0.000373 AC: 2 AN: 5368

European-Non Finnish (NFE) AF: 0.000773 AC: 820 AN: 1061016

Other (OTH) AF: 0.000359 AC: 20 AN: 55732

GnomAD4 genome AF: 0.000481 AC: 73 AN: 151846 Hom.: 0 Cov.: 32 AF XY: 0.000445 AC XY: 33 AN XY: 74194

African (AFR) AF: 0.0000965 AC: 4 AN: 41460

American (AMR) AF: 0.000197 AC: 3 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10542

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

European-Non Finnish (NFE) AF: 0.000854 AC: 58 AN: 67918

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000561 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000863 AC: 7

ExAC AF: 0.000337 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	3	not specified (4)
-	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	Tibial muscular dystrophy (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Benign	0.96
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.33
MVP		0.83
MPC		0.24
ClinPred		0.32	T
GERP RS		4.9
Mutation Taster		=87/13	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: rs201035511; hg19: chr2-179467311;