2-178735658-G-T

Variant names:

• chr2-178735658-G-T
• rs201744218
• NM_001267550.2:c.14788C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.14788C>A​(p.Pro4930Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,684 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4930A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 3.80
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021382868).
• BP6: Variant 2-178735658-G-T is Benign according to our data. Variant chr2-178735658-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203241.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000643 (94/1461466) while in subpopulation AFR AF = 0.00245 (82/33472). AF 95% confidence interval is 0.00202. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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.14788C>A	p.Pro4930Thr	missense	Exon 50 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.13837C>A	p.Pro4613Thr	missense	Exon 48 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.11056C>A	p.Pro3686Thr	missense	Exon 47 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.14788C>A	p.Pro4930Thr	missense	Exon 50 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.14788C>A	p.Pro4930Thr	missense	Exon 50 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.14512C>A	p.Pro4838Thr	missense	Exon 48 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.000478

GnomAD2 exomes AF: 0.000133 AC: 33 AN: 248544 AF XY: 0.0000964

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461466 Hom.: 0 Cov.: 29 AF XY: 0.0000454 AC XY: 33 AN XY: 726996

African (AFR) AF: 0.00245 AC: 82 AN: 33472

American (AMR) AF: 0.000134 AC: 6 AN: 44716

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111784

Other (OTH) AF: 0.0000828 AC: 5 AN: 60354

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74420

African (AFR) AF: 0.00159 AC: 66 AN: 41548

American (AMR) AF: 0.000458 AC: 7 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000703

ESP6500AA AF: 0.00190 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.82
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.77	T
PhyloP100		3.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.11
Sift	Benign	0.087	T
Polyphen		0.0020	B
Vest4		0.23
MVP		0.41
MPC		0.095
ClinPred		0.019	T
GERP RS		1.6
Mutation Taster		=78/22	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: rs201744218; hg19: chr2-179600385;