rs146181116

Variant names:

• chr2-178555065-G-A
• rs146181116
• NM_001267550.2:c.88394C>T

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.88394C>T​(p.Ser29465Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,613,780 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (19 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:23
• Conservation: PhyloP100: 2.18
• Publications: 12 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008737415).
• BP6: Variant 2-178555065-G-A is Benign according to our data. Variant chr2-178555065-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47477.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00325 (495/152256) while in subpopulation NFE AF = 0.00556 (378/68010). AF 95% confidence interval is 0.0051. There are 0 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 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.88394C>T	p.Ser29465Phe	missense	Exon 331 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.83471C>T	p.Ser27824Phe	missense	Exon 281 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.80690C>T	p.Ser26897Phe	missense	Exon 280 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.88394C>T	p.Ser29465Phe	missense	Exon 331 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.88238C>T	p.Ser29413Phe	missense	Exon 329 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.88118C>T	p.Ser29373Phe	missense	Exon 329 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 495 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00519

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00293 AC: 727 AN: 248266 AF XY: 0.00299

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00645

Gnomad NFE exome AF: 0.00440

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00381 AC: 5565 AN: 1461524 Hom.: 19 Cov.: 32 AF XY: 0.00378 AC XY: 2748 AN XY: 727050

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.00134 AC: 60 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86250

European-Finnish (FIN) AF: 0.00706 AC: 377 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00440 AC: 4893 AN: 1111798

Other (OTH) AF: 0.00249 AC: 150 AN: 60356

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00306 AC XY: 228 AN XY: 74436

African (AFR) AF: 0.000770 AC: 32 AN: 41562

American (AMR) AF: 0.00144 AC: 22 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00519 AC: 55 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00417 Hom.: 6

Bravo AF: 0.00240

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.00449 AC: 37

ExAC AF: 0.00271 AC: 328

EpiCase AF: 0.00447

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	5	not provided (5)
-	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	Hypertrophic cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.55	T
Polyphen		0.99	D
Vest4		0.49
MVP		0.53
MPC		0.35
ClinPred		0.030	T
GERP RS		5.7
Mutation Taster		=100/0	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: rs146181116; hg19: chr2-179419792;