chr2-178717115-G-A

Variant names:

• chr2-178717115-G-A
• rs201523784
• NM_001267550.2:c.25619C>T

Variant summary

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

The NM_001267550.2(TTN):​c.25619C>T​(p.Ser8540Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,613,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11
• Conservation: PhyloP100: 1.12
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015490621).
• BP6: Variant 2-178717115-G-A is Benign according to our data. Variant chr2-178717115-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46762.

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.25619C>T	p.Ser8540Phe	missense	Exon 88 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.24668C>T	p.Ser8223Phe	missense	Exon 86 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.21887C>T	p.Ser7296Phe	missense	Exon 85 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.25619C>T	p.Ser8540Phe	missense	Exon 88 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.25619C>T	p.Ser8540Phe	missense	Exon 88 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.25343C>T	p.Ser8448Phe	missense	Exon 86 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000576 AC: 143 AN: 248154 AF XY: 0.000505

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000650

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000622 AC: 908 AN: 1460766 Hom.: 1 Cov.: 31 AF XY: 0.000579 AC XY: 421 AN XY: 726616

African (AFR) AF: 0.0000598 AC: 2 AN: 33426

American (AMR) AF: 0.000470 AC: 21 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86144

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53352

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

European-Non Finnish (NFE) AF: 0.000639 AC: 710 AN: 1111282

Other (OTH) AF: 0.000812 AC: 49 AN: 60324

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74456

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000760 Hom.: 1

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000605 AC: 5

ExAC AF: 0.000505 AC: 61

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	not specified (3)
-	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	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 9 (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	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.0063
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.66	T
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Polyphen		0.0	B
Vest4		0.31
MVP		0.50
MPC		0.092
ClinPred		0.028	T
GERP RS		2.5
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201523784; hg19: chr2-179581842; COSMIC: COSV59928504; COSMIC: COSV59928504;