rs186244950

Variant names:

• chr2-178539460-G-A
• rs186244950
• NM_001267550.2:c.98605C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178539460-G-A
• chr2-178539460-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM5 BP4_Moderate BP6

The NM_001267550.2(TTN):​c.98605C>T​(p.Arg32869Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R32869H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 7.10
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-178539459-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 130686.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07545617).
• BP6: Variant 2-178539460-G-A is Benign according to our data. Variant chr2-178539460-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203040.

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.98605C>T	p.Arg32869Cys	missense	Exon 352 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.93682C>T	p.Arg31228Cys	missense	Exon 302 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.90901C>T	p.Arg30301Cys	missense	Exon 301 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.98605C>T	p.Arg32869Cys	missense	Exon 352 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.98449C>T	p.Arg32817Cys	missense	Exon 350 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.98329C>T	p.Arg32777Cys	missense	Exon 350 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000221 AC: 55 AN: 248954 AF XY: 0.000215

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1461552 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 98 AN XY: 727062

African (AFR) AF: 0.000359 AC: 12 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111766

Other (OTH) AF: 0.000215 AC: 13 AN: 60364

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74440

African (AFR) AF: 0.000169 AC: 7 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.000364 AC: 3

ExAC AF: 0.000182 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	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	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Benign	0.95
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.075	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.79
MPC		0.52
ClinPred		0.23	T
GERP RS		5.7
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs186244950; hg19: chr2-179404187; COSMIC: COSV60424927; COSMIC: COSV60424927;