2-178682738-C-T

Variant names:

• chr2-178682738-C-T
• rs72650034
• NM_001267550.2:c.33053G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.33053G>A​(p.Arg11018Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,612,752 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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. R11018W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (12 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:14
• Conservation: PhyloP100: 0.312
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003914356).
• BP6: Variant 2-178682738-C-T is Benign according to our data. Variant chr2-178682738-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46882.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.33053G>A	p.Arg11018Gln	missense	Exon 135 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.32102G>A	p.Arg10701Gln	missense	Exon 133 of 313	NP_001243779.1
	TTN	NM_133378.4		c.29321G>A	p.Arg9774Gln	missense	Exon 132 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.33053G>A	p.Arg11018Gln	missense	Exon 135 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.33053G>A	p.Arg11018Gln	missense	Exon 135 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.32777G>A	p.Arg10926Gln	missense	Exon 133 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000922 AC: 140 AN: 151820 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000973

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000812 AC: 202 AN: 248694 AF XY: 0.000741

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00106

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000792 AC: 1157 AN: 1460814 Hom.: 12 Cov.: 31 AF XY: 0.000775 AC XY: 563 AN XY: 726664

African (AFR) AF: 0.000717 AC: 24 AN: 33454

American (AMR) AF: 0.000671 AC: 30 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00284 AC: 74 AN: 26102

East Asian (EAS) AF: 0.000832 AC: 33 AN: 39650

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86120

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53360

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5760

European-Non Finnish (NFE) AF: 0.000696 AC: 773 AN: 1111340

Other (OTH) AF: 0.00323 AC: 195 AN: 60322

GnomAD4 genome AF: 0.000921 AC: 140 AN: 151938 Hom.: 1 Cov.: 32 AF XY: 0.000741 AC XY: 55 AN XY: 74262

African (AFR) AF: 0.000722 AC: 30 AN: 41524

American (AMR) AF: 0.000722 AC: 11 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000974 AC: 66 AN: 67794

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00131 Hom.: 4

Bravo AF: 0.00117

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000794 AC: 3

ESP6500EA AF: 0.00110 AC: 9

ExAC AF: 0.000836 AC: 101

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	3	not specified (3)
-	-	2	Tibial muscular dystrophy (2)
-	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	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.61
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.31
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.078
Sift	Benign	0.30	T
Polyphen		0.18	B
Vest4		0.20
MVP		0.061
MPC		0.10
ClinPred		0.0030	T
GERP RS		2.2
Mutation Taster		=95/5	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: rs72650034; hg19: chr2-179547465; COSMIC: COSV108177993;