rs201888760

Variant names:

• chr2-178741088-G-A
• rs201888760
• NM_001267550.2:c.12145C>T

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.12145C>T​(p.Pro4049Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,880 control chromosomes in the GnomAD database, including 2 homozygotes. 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).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 0.258
• Publications: 5 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=0.0190306).
• BP6: Variant 2-178741088-G-A is Benign according to our data. Variant chr2-178741088-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47817.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000304 (444/1461576) while in subpopulation MID AF = 0.00451 (26/5766). AF 95% confidence interval is 0.00316. There are 1 homozygotes in GnomAdExome4. There are 252 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. 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.12145C>T	p.Pro4049Ser	missense	Exon 48 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.11194C>T	p.Pro3732Ser	missense	Exon 46 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133437.4		c.11632C>T	p.Pro3878Ser	missense	Exon 46 of 192	NP_597681.4	A0A0A0MRA3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.12145C>T	p.Pro4049Ser	missense	Exon 48 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.12145C>T	p.Pro4049Ser	missense	Exon 48 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11869C>T	p.Pro3957Ser	missense	Exon 46 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000387 AC: 96 AN: 248296 AF XY: 0.000379

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000526

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1461576 Hom.: 1 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 727074

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26130

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

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5766

European-Non Finnish (NFE) AF: 0.000273 AC: 304 AN: 1111812

Other (OTH) AF: 0.000381 AC: 23 AN: 60368

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74458

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68018

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

Alfa AF: 0.000260 Hom.: 1

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000480 AC: 58

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	1	2	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.8
DANN	Benign	0.67
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.26
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.065
Sift	Pathogenic	0.0	D
Vest4		0.042
MVP		0.040
MPC		0.084
ClinPred		0.019	T
GERP RS		-0.66
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: rs201888760; hg19: chr2-179605815; COSMIC: COSV60084222; COSMIC: COSV60084222;