chr2-178714164-T-C

Variant names:

• chr2-178714164-T-C
• rs72648989
• NM_001267550.2:c.26494A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.26494A>G​(p.Ile8832Val) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,610,370 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I8832T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:11
• Conservation: PhyloP100: 3.86
• Publications: 8 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045123607).
• BP6: Variant 2-178714164-T-C is Benign according to our data. Variant chr2-178714164-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177972.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00146 (2124/1458096) while in subpopulation NFE AF = 0.00173 (1919/1110296). AF 95% confidence interval is 0.00166. There are 3 homozygotes in GnomAdExome4. There are 1052 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.26494A>G	p.Ile8832Val	missense	Exon 92 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25543A>G	p.Ile8515Val	missense	Exon 90 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.22762A>G	p.Ile7588Val	missense	Exon 89 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.26494A>G	p.Ile8832Val	missense	Exon 92 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26494A>G	p.Ile8832Val	missense	Exon 92 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26218A>G	p.Ile8740Val	missense	Exon 90 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000773 AC: 190 AN: 245890 AF XY: 0.000788

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000839

GnomAD4 exome AF: 0.00146 AC: 2124 AN: 1458096 Hom.: 3 Cov.: 34 AF XY: 0.00145 AC XY: 1052 AN XY: 724898

African (AFR) AF: 0.000301 AC: 10 AN: 33190

American (AMR) AF: 0.000181 AC: 8 AN: 44282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00110 AC: 94 AN: 85354

European-Finnish (FIN) AF: 0.000581 AC: 31 AN: 53370

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5740

European-Non Finnish (NFE) AF: 0.00173 AC: 1919 AN: 1110296

Other (OTH) AF: 0.000931 AC: 56 AN: 60180

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.000793 AC XY: 59 AN XY: 74444

African (AFR) AF: 0.000361 AC: 15 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68020

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

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.000774

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000981 AC: 8

ExAC AF: 0.000820 AC: 99

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	5	not provided (9)
-	2	2	not specified (4)
-	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	-	Distal myopathy (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.94
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.30	T
PhyloP100		3.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.14
Sift	Benign	0.52	T
Polyphen		0.91	P
Vest4		0.13
MVP		0.66
MPC		0.23
ClinPred		0.037	T
GERP RS		5.9
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72648989; hg19: chr2-179578891;