rs772625773

Variant names:

• chr2-178617387-C-T
• rs772625773
• NM_001267550.2:c.47698G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001267550.2(TTN):​c.47698G>A​(p.Glu15900Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,436,846 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. E15900E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.86
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42091364).
• BP6: Variant 2-178617387-C-T is Benign according to our data. Variant chr2-178617387-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 451886.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.47698G>A	p.Glu15900Lys	missense	Exon 254 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.42775G>A	p.Glu14259Lys	missense	Exon 204 of 313	NP_001243779.1
	TTN	NM_133378.4		c.39994G>A	p.Glu13332Lys	missense	Exon 203 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.47698G>A	p.Glu15900Lys	missense	Exon 254 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.47542G>A	p.Glu15848Lys	missense	Exon 252 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.47422G>A	p.Glu15808Lys	missense	Exon 252 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000368 AC: 8 AN: 217312 AF XY: 0.0000341

Gnomad AFR exome AF: 0.0000724

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000504

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 28 AN: 1436846 Hom.: 0 Cov.: 32 AF XY: 0.0000154 AC XY: 11 AN XY: 713136

African (AFR) AF: 0.0000310 AC: 1 AN: 32306

American (AMR) AF: 0.00 AC: 0 AN: 39392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39082

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000209 AC: 23 AN: 1102482

Other (OTH) AF: 0.0000168 AC: 1 AN: 59408

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000438 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000332 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.43
Sift	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.60		Gain of methylation at E14259 (P = 0.0051)
MVP		0.44
MPC		0.49
ClinPred		0.14	T
GERP RS		5.9
Mutation Taster		=79/21	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: rs772625773; hg19: chr2-179482114; COSMIC: COSV60190620; COSMIC: COSV60190620;