2-178713914-G-C

Variant names:

• chr2-178713914-G-C
• rs536974988
• NM_001267550.2:c.26744C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.26744C>G​(p.Ala8915Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 3.33
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16473329).

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.26744C>G	p.Ala8915Gly	missense	Exon 92 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.25793C>G	p.Ala8598Gly	missense	Exon 90 of 313	NP_001243779.1
	TTN	NM_133378.4		c.23012C>G	p.Ala7671Gly	missense	Exon 89 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.26744C>G	p.Ala8915Gly	missense	Exon 92 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.26744C>G	p.Ala8915Gly	missense	Exon 92 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.26468C>G	p.Ala8823Gly	missense	Exon 90 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248246 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461008 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726738

African (AFR) AF: 0.0000299 AC: 1 AN: 33430

American (AMR) AF: 0.0000224 AC: 1 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111422

Other (OTH) AF: 0.000232 AC: 14 AN: 60352

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74442

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	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	-	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	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.86
Eigen	Benign	-0.043
Eigen_PC	Benign	0.079
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.67	T
PhyloP100		3.3
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D
Polyphen		0.12	B
Vest4		0.14
MutPred		0.60		Gain of methylation at K8593 (P = 0.0676)
MVP		0.26
MPC		0.12
ClinPred		0.16	T
GERP RS		4.0
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs536974988; hg19: chr2-179578641;