rs72647902

Variant names:

• chr2-178749277-C-A
• rs72647902
• NM_001267550.2:c.11311+3847G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178749277-C-A
• chr2-178749277-C-G
• chr2-178749277-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_133379.5(TTN):​c.13123G>T​(p.Ala4375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,611,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 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 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.226
• Publications: 9 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017016172).
• BP6: Variant 2-178749277-C-A is Benign according to our data. Variant chr2-178749277-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47748.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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.11311+3847G>T		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.13123G>T	p.Ala4375Ser	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10360+3847G>T		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+3847G>T		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+3847G>T		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+3847G>T		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000314 AC: 78 AN: 248520 AF XY: 0.000312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000437

Gnomad NFE exome AF: 0.000498

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000562 AC: 820 AN: 1459344 Hom.: 0 Cov.: 35 AF XY: 0.000522 AC XY: 379 AN XY: 726070

African (AFR) AF: 0.000120 AC: 4 AN: 33424

American (AMR) AF: 0.000291 AC: 13 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.000270 AC: 14 AN: 51804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000689 AC: 766 AN: 1111420

Other (OTH) AF: 0.000381 AC: 23 AN: 60328

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74336

African (AFR) AF: 0.0000963 AC: 4 AN: 41526

American (AMR) AF: 0.000328 AC: 5 AN: 15244

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000648 Hom.: 1

Bravo AF: 0.000389

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000546

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	2	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	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.23
PROVEAN	Benign	0.34	N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.74	T
Polyphen		0.082	B
Vest4		0.24
MVP		0.44
ClinPred		0.080	T
GERP RS		4.2
Mutation Taster		=100/0	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: rs72647902; hg19: chr2-179614004; COSMIC: COSV104645670; COSMIC: COSV104645670;