rs55866005

Variant names:

• chr2-178532055-C-G
• rs55866005
• NM_001267550.2:c.104560G>C

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.104560G>C​(p.Val34854Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00678 in 1,613,942 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. V34854G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (42 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:24
• Conservation: PhyloP100: 4.84
• Publications: 9 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050283074).
• BP6: Variant 2-178532055-C-G is Benign according to our data. Variant chr2-178532055-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47674.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0052 (792/152296) while in subpopulation NFE AF = 0.00881 (599/68024). AF 95% confidence interval is 0.00822. There are 3 homozygotes in GnomAd4. There are 365 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.104560G>C	p.Val34854Leu	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.99637G>C	p.Val33213Leu	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.96856G>C	p.Val32286Leu	missense	Exon 307 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.104560G>C	p.Val34854Leu	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.104404G>C	p.Val34802Leu	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.104284G>C	p.Val34762Leu	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00879

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00537 AC: 1336 AN: 248872 AF XY: 0.00546

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00846

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.00647

GnomAD4 exome AF: 0.00694 AC: 10149 AN: 1461646 Hom.: 42 Cov.: 40 AF XY: 0.00684 AC XY: 4975 AN XY: 727108

African (AFR) AF: 0.00105 AC: 35 AN: 33476

American (AMR) AF: 0.00228 AC: 102 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86256

European-Finnish (FIN) AF: 0.00710 AC: 379 AN: 53386

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.00812 AC: 9032 AN: 1111844

Other (OTH) AF: 0.00601 AC: 363 AN: 60374

GnomAD4 genome AF: 0.00520 AC: 792 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00490 AC XY: 365 AN XY: 74480

African (AFR) AF: 0.00140 AC: 58 AN: 41558

American (AMR) AF: 0.00157 AC: 24 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

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

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00881 AC: 599 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00742 Hom.: 1

Bravo AF: 0.00445

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000487 AC: 2

ESP6500EA AF: 0.00903 AC: 76

ExAC AF: 0.00495 AC: 599

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00729

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	13	not specified (13)
-	1	4	not provided (5)
-	-	2	Cardiomyopathy (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	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	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.85
Eigen	Benign	-0.13
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Uncertain	0.010	D
Polyphen		0.039	B
Vest4		0.16
MutPred		0.18		Loss of MoRF binding (P = 0.0918)
MVP		0.43
MPC		0.084
ClinPred		0.013	T
GERP RS		4.7
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: rs55866005; hg19: chr2-179396782;