rs55663050

Variant names:

• chr2-178612802-C-G
• rs55663050
• NM_001267550.2:c.49919G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178612802-C-G
• chr2-178612802-C-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.49919G>C​(p.Ser16640Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,612,008 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0018 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (48 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: 7.86
• Publications: 10 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=0.0046233535).
• BP6: Variant 2-178612802-C-G is Benign according to our data. Variant chr2-178612802-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47036.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00182 (276/151994) while in subpopulation SAS AF = 0.0245 (118/4808). AF 95% confidence interval is 0.0209. There are 5 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.49919G>C	p.Ser16640Thr	missense	Exon 265 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.44996G>C	p.Ser14999Thr	missense	Exon 215 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.42215G>C	p.Ser14072Thr	missense	Exon 214 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.49919G>C	p.Ser16640Thr	missense	Exon 265 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.49763G>C	p.Ser16588Thr	missense	Exon 263 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.49643G>C	p.Ser16548Thr	missense	Exon 263 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 151876 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0239

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00375 AC: 924 AN: 246610 AF XY: 0.00476

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.0000567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.00224 AC: 3269 AN: 1460014 Hom.: 48 Cov.: 33 AF XY: 0.00285 AC XY: 2073 AN XY: 726256

African (AFR) AF: 0.000419 AC: 14 AN: 33398

American (AMR) AF: 0.000695 AC: 31 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.000843 AC: 22 AN: 26082

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39404

South Asian (SAS) AF: 0.0211 AC: 1815 AN: 86084

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53346

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5752

European-Non Finnish (NFE) AF: 0.00105 AC: 1171 AN: 1111072

Other (OTH) AF: 0.00299 AC: 180 AN: 60270

GnomAD4 genome AF: 0.00182 AC: 276 AN: 151994 Hom.: 5 Cov.: 32 AF XY: 0.00209 AC XY: 155 AN XY: 74276

African (AFR) AF: 0.000241 AC: 10 AN: 41524

American (AMR) AF: 0.00184 AC: 28 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 67906

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

Alfa AF: 0.00168 Hom.: 1

Bravo AF: 0.00105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000520 AC: 2

ESP6500EA AF: 0.00192 AC: 16

ExAC AF: 0.00432 AC: 522

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00267

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	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.92
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0046	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.38
MPC		0.44
ClinPred		0.049	T
GERP RS		5.7
Mutation Taster		=98/2	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: rs55663050; hg19: chr2-179477529;