rs200650668

Variant names:

• chr2-178609501-C-A
• rs200650668
• NM_001267550.2:c.51809G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178609501-C-A
• chr2-178609501-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000589042.5(TTN):​c.51809G>T​(p.Ser17270Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,612,560 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (4 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:14
• Conservation: PhyloP100: 1.96
• Publications: 7 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017699331).
• BP6: Variant 2-178609501-C-A is Benign according to our data. Variant chr2-178609501-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47057.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.51809G>T	p.Ser17270Ile	missense	Exon 273 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.46886G>T	p.Ser15629Ile	missense	Exon 223 of 313	NP_001243779.1
	TTN	NM_133378.4		c.44105G>T	p.Ser14702Ile	missense	Exon 222 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.51809G>T	p.Ser17270Ile	missense	Exon 273 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.51653G>T	p.Ser17218Ile	missense	Exon 271 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.51533G>T	p.Ser17178Ile	missense	Exon 271 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 151916 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000898

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000416 AC: 103 AN: 247482 AF XY: 0.000454

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000859

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000846 AC: 1236 AN: 1460526 Hom.: 4 Cov.: 32 AF XY: 0.000794 AC XY: 577 AN XY: 726560

African (AFR) AF: 0.000120 AC: 4 AN: 33406

American (AMR) AF: 0.000112 AC: 5 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00108 AC: 1201 AN: 1111234

Other (OTH) AF: 0.000415 AC: 25 AN: 60294

GnomAD4 genome AF: 0.000454 AC: 69 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74308

African (AFR) AF: 0.000144 AC: 6 AN: 41528

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000898 AC: 61 AN: 67920

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000742 Hom.: 1

Bravo AF: 0.000465

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000529 AC: 2

ESP6500EA AF: 0.000850 AC: 7

ExAC AF: 0.000480 AC: 58

EpiCase AF: 0.000710

EpiControl AF: 0.000357

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	6	not provided (9)
-	-	4	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.87
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.095
Sift	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.091
MVP		0.27
MPC		0.099
ClinPred		0.045	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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: rs200650668; hg19: chr2-179474228;