2-178607592-C-T

Variant names:

• chr2-178607592-C-T
• rs72646808
• NM_001267550.2:c.53096G>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.53096G>A​(p.Arg17699His) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,613,116 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R17699C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:15
• Conservation: PhyloP100: 4.49
• Publications: 17 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=0.015400916).
• BP6: Variant 2-178607592-C-T is Benign according to our data. Variant chr2-178607592-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47070.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00159 (241/152038) while in subpopulation NFE AF = 0.00258 (175/67920). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.53096G>A	p.Arg17699His	missense	Exon 277 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.48173G>A	p.Arg16058His	missense	Exon 227 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45392G>A	p.Arg15131His	missense	Exon 226 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.53096G>A	p.Arg17699His	missense	Exon 277 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52940G>A	p.Arg17647His	missense	Exon 275 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52820G>A	p.Arg17607His	missense	Exon 275 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 241 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000584

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00258

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00185 AC: 457 AN: 247686 AF XY: 0.00187

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.000725

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00231 AC: 3375 AN: 1461078 Hom.: 3 Cov.: 32 AF XY: 0.00235 AC XY: 1707 AN XY: 726846

African (AFR) AF: 0.000419 AC: 14 AN: 33432

American (AMR) AF: 0.00114 AC: 51 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26124

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39668

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86248

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53348

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00268 AC: 2981 AN: 1111456

Other (OTH) AF: 0.00169 AC: 102 AN: 60330

GnomAD4 genome AF: 0.00159 AC: 241 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 74310

African (AFR) AF: 0.000674 AC: 28 AN: 41514

American (AMR) AF: 0.00138 AC: 21 AN: 15262

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

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5122

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00258 AC: 175 AN: 67920

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00249 Hom.: 3

Bravo AF: 0.00180

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000533 AC: 2

ESP6500EA AF: 0.00304 AC: 25

ExAC AF: 0.00197 AC: 238

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	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)
1	-	-	Tip-toe gait (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.92
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.52
MPC		0.50
ClinPred		0.043	T
GERP RS		6.0
Mutation Taster		=92/8	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: rs72646808; hg19: chr2-179472319; COSMIC: COSV59914507; COSMIC: COSV59914507;