rs571328201

Variant names:

• chr2-178565466-T-C
• rs571328201
• NM_001267550.2:c.80666A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178565466-T-C
• chr2-178565466-T-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001267550.2(TTN):​c.80666A>G​(p.Tyr26889Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,613,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y26889Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 4.92
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37097055).

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.80666A>G	p.Tyr26889Cys	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.75743A>G	p.Tyr25248Cys	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.72962A>G	p.Tyr24321Cys	missense	Exon 275 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.80666A>G	p.Tyr26889Cys	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.80510A>G	p.Tyr26837Cys	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.80390A>G	p.Tyr26797Cys	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000125 AC: 31 AN: 248430 AF XY: 0.000156

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1461126 Hom.: 0 Cov.: 37 AF XY: 0.000132 AC XY: 96 AN XY: 726868

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.0000224 AC: 1 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000148 AC: 165 AN: 1111604

Other (OTH) AF: 0.0000497 AC: 3 AN: 60338

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74306

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	1	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.89
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.68
MPC		0.50
ClinPred		0.50	D
GERP RS		5.5
Mutation Taster		=52/48	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: rs571328201; hg19: chr2-179430193;