2-178552364-C-T

Variant names:

• chr2-178552364-C-T
• rs149567378
• NM_001267550.2:c.90536G>A

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.90536G>A​(p.Arg30179His) variant causes a missense change. The variant allele was found at a frequency of 0.00217 in 1,592,798 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts 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. R30179G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: 6.17
• Publications: 11 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=0.006216377).
• BP6: Variant 2-178552364-C-T is Benign according to our data. Variant chr2-178552364-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47497.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00185 (282/152234) while in subpopulation SAS AF = 0.0243 (117/4820). AF 95% confidence interval is 0.0207. There are 5 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.90536G>A	p.Arg30179His	missense	Exon 335 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.85613G>A	p.Arg28538His	missense	Exon 285 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.82832G>A	p.Arg27611His	missense	Exon 284 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.90536G>A	p.Arg30179His	missense	Exon 335 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.90380G>A	p.Arg30127His	missense	Exon 333 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.90260G>A	p.Arg30087His	missense	Exon 333 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152116 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00354 AC: 820 AN: 231574 AF XY: 0.00451

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.000953

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00357

GnomAD4 exome AF: 0.00220 AC: 3173 AN: 1440564 Hom.: 47 Cov.: 33 AF XY: 0.00281 AC XY: 2004 AN XY: 713952

African (AFR) AF: 0.000396 AC: 13 AN: 32846

American (AMR) AF: 0.000818 AC: 35 AN: 42788

Ashkenazi Jewish (ASJ) AF: 0.000845 AC: 21 AN: 24856

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39392

South Asian (SAS) AF: 0.0210 AC: 1726 AN: 82030

European-Finnish (FIN) AF: 0.0000570 AC: 3 AN: 52610

Middle Eastern (MID) AF: 0.00441 AC: 25 AN: 5666

European-Non Finnish (NFE) AF: 0.00106 AC: 1163 AN: 1100984

Other (OTH) AF: 0.00301 AC: 179 AN: 59392

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152234 Hom.: 5 Cov.: 33 AF XY: 0.00214 AC XY: 159 AN XY: 74414

African (AFR) AF: 0.000241 AC: 10 AN: 41556

American (AMR) AF: 0.00183 AC: 28 AN: 15272

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0243 AC: 117 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00170 Hom.: 1

Bravo AF: 0.00107

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000531 AC: 2

ESP6500EA AF: 0.00195 AC: 16

ExAC AF: 0.00423 AC: 511

Asia WGS AF: 0.0130 AC: 46 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	6	not provided (7)
-	-	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	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.93
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.41
MVP		0.37
MPC		0.52
ClinPred		0.044	T
GERP RS		5.8
Mutation Taster		=99/1	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: rs149567378; hg19: chr2-179417091;