rs73973137

Variant names:

• chr2-178684055-G-A
• rs73973137
• NM_001267550.2:c.32750C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178684055-G-A
• chr2-178684055-G-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.32750C>T​(p.Pro10917Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000542 in 1,609,910 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. P10917Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (5 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 3.93
• Publications: 3 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010159224).
• BP6: Variant 2-178684055-G-A is Benign according to our data. Variant chr2-178684055-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46878.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00282 (424/150326) while in subpopulation AFR AF = 0.01 (411/40902). AF 95% confidence interval is 0.00925. There are 1 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.32750C>T	p.Pro10917Leu	missense	Exon 133 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31799C>T	p.Pro10600Leu	missense	Exon 131 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.29018C>T	p.Pro9673Leu	missense	Exon 130 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.32750C>T	p.Pro10917Leu	missense	Exon 133 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32750C>T	p.Pro10917Leu	missense	Exon 133 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32474C>T	p.Pro10825Leu	missense	Exon 131 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 423 AN: 150222 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.000974

GnomAD2 exomes AF: 0.000708 AC: 176 AN: 248426 AF XY: 0.000512

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000307 AC: 448 AN: 1459584 Hom.: 5 Cov.: 32 AF XY: 0.000258 AC XY: 187 AN XY: 726042

African (AFR) AF: 0.0115 AC: 385 AN: 33408

American (AMR) AF: 0.000538 AC: 24 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110700

Other (OTH) AF: 0.000498 AC: 30 AN: 60290

GnomAD4 genome AF: 0.00282 AC: 424 AN: 150326 Hom.: 1 Cov.: 31 AF XY: 0.00265 AC XY: 194 AN XY: 73288

African (AFR) AF: 0.0100 AC: 411 AN: 40902

American (AMR) AF: 0.000529 AC: 8 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10120

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

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67584

Other (OTH) AF: 0.000964 AC: 2 AN: 2074

Alfa AF: 0.000970 Hom.: 5

Bravo AF: 0.00331

ESP6500AA AF: 0.00942 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000786 AC: 95

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	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	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.94
Eigen	Benign	0.039
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.56	T
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D
Polyphen		0.010	B
Vest4		0.38
MVP		0.62
MPC		0.088
ClinPred		0.031	T
GERP RS		5.6
Mutation Taster		=60/40	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: rs73973137; hg19: chr2-179548782;