2-178601444-T-C

Variant names:

• chr2-178601444-T-C
• rs72646823
• NM_001267550.2:c.55553A>G

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.55553A>G​(p.Lys18518Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,612,960 control chromosomes in the GnomAD database, including 8 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 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16
• Conservation: PhyloP100: 6.21
• Publications: 14 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=0.008680731).
• BP6: Variant 2-178601444-T-C is Benign according to our data. Variant chr2-178601444-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47106.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0025 (380/152076) while in subpopulation AFR AF = 0.00592 (246/41526). AF 95% confidence interval is 0.00532. There are 2 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.55553A>G	p.Lys18518Arg	missense	Exon 287 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.50630A>G	p.Lys16877Arg	missense	Exon 237 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.47849A>G	p.Lys15950Arg	missense	Exon 236 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.55553A>G	p.Lys18518Arg	missense	Exon 287 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.55397A>G	p.Lys18466Arg	missense	Exon 285 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.55277A>G	p.Lys18426Arg	missense	Exon 285 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 381 AN: 151958 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00162 AC: 403 AN: 248382 AF XY: 0.00151

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000551

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.000934 AC: 1365 AN: 1460884 Hom.: 6 Cov.: 32 AF XY: 0.000970 AC XY: 705 AN XY: 726732

African (AFR) AF: 0.00616 AC: 206 AN: 33434

American (AMR) AF: 0.00139 AC: 62 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 446 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00764 AC: 44 AN: 5762

European-Non Finnish (NFE) AF: 0.000395 AC: 439 AN: 1111414

Other (OTH) AF: 0.00244 AC: 147 AN: 60342

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152076 Hom.: 2 Cov.: 32 AF XY: 0.00264 AC XY: 196 AN XY: 74334

African (AFR) AF: 0.00592 AC: 246 AN: 41526

American (AMR) AF: 0.00269 AC: 41 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67940

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00149 Hom.: 4

Bravo AF: 0.00289

ESP6500AA AF: 0.00359 AC: 14

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.00137 AC: 165

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000874

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.92
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.36
MVP		0.36
MPC		0.42
ClinPred		0.034	T
GERP RS		5.8
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: rs72646823; hg19: chr2-179466171;