rs73973133

Variant names:

• chr2-178664080-T-A
• rs73973133
• NM_001267550.2:c.36299A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.36299A>T​(p.Glu12100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,612,090 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E12100E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (155 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (155 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.30
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022535026).
• BP6: Variant 2-178664080-T-A is Benign according to our data. Variant chr2-178664080-T-A is described in ClinVar as Benign. ClinVar VariationId is 192217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

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.36299A>T	p.Glu12100Val	missense	Exon 169 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34265-1025A>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31484-1025A>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.36299A>T	p.Glu12100Val	missense	Exon 169 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.36299A>T	p.Glu12100Val	missense	Exon 169 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.36023A>T	p.Glu12008Val	missense	Exon 167 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3868 AN: 152062 Hom.: 155 Cov.: 31

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00653 AC: 1584 AN: 242702 AF XY: 0.00477

Gnomad AFR exome AF: 0.0938

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00285 AC: 4155 AN: 1459910 Hom.: 155 Cov.: 33 AF XY: 0.00252 AC XY: 1832 AN XY: 726248

African (AFR) AF: 0.0970 AC: 3234 AN: 33328

American (AMR) AF: 0.00518 AC: 230 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52874

Middle Eastern (MID) AF: 0.00505 AC: 29 AN: 5746

European-Non Finnish (NFE) AF: 0.000252 AC: 280 AN: 1111504

Other (OTH) AF: 0.00606 AC: 365 AN: 60274

GnomAD4 genome AF: 0.0254 AC: 3871 AN: 152180 Hom.: 155 Cov.: 31 AF XY: 0.0243 AC XY: 1811 AN XY: 74400

African (AFR) AF: 0.0875 AC: 3632 AN: 41520

American (AMR) AF: 0.0111 AC: 170 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67988

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.00795 Hom.: 14

Bravo AF: 0.0292

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0765 AC: 134

ESP6500EA AF: 0.000251 AC: 1

ExAC AF: 0.00734 AC: 868

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	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	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
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
Vest4		0.27
MVP		0.71
MPC		0.31
ClinPred		0.0090	T
GERP RS		1.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs73973133; hg19: chr2-179528807;