rs72650053

Variant names:

• chr2-178663341-C-A
• rs72650053
• NM_001267550.2:c.36625G>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.36625G>T​(p.Val12209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,588,700 control chromosomes in the GnomAD database, including 1,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 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. V12209V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (57 hom., cov: 29)
  • Exomes 𝑓: 0.010 (1280 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.385
• Publications: 5 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=0.0014425218).
• BP6: Variant 2-178663341-C-A is Benign according to our data. Variant chr2-178663341-C-A is described in ClinVar as Benign. ClinVar VariationId is 192214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 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.36625G>T	p.Val12209Leu	missense	Exon 173 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34265-286G>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31484-286G>T		intron	N/A	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.36625G>T	p.Val12209Leu	missense	Exon 173 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36625G>T	p.Val12209Leu	missense	Exon 173 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36349G>T	p.Val12117Leu	missense	Exon 171 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2075 AN: 146308 Hom.: 56 Cov.: 29

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00347

Gnomad AMR AF: 0.00514

Gnomad ASJ AF: 0.0214

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.0151

GnomAD2 exomes AF: 0.0234 AC: 5452 AN: 232644 AF XY: 0.0239

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0103 AC: 14884 AN: 1442274 Hom.: 1280 Cov.: 34 AF XY: 0.0113 AC XY: 8135 AN XY: 716784

African (AFR) AF: 0.0161 AC: 527 AN: 32706

American (AMR) AF: 0.00417 AC: 175 AN: 41944

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 593 AN: 25740

East Asian (EAS) AF: 0.141 AC: 5380 AN: 38058

South Asian (SAS) AF: 0.0418 AC: 3424 AN: 81834

European-Finnish (FIN) AF: 0.0270 AC: 1431 AN: 52930

Middle Eastern (MID) AF: 0.0166 AC: 68 AN: 4086

European-Non Finnish (NFE) AF: 0.00211 AC: 2332 AN: 1105440

Other (OTH) AF: 0.0160 AC: 954 AN: 59536

GnomAD4 genome AF: 0.0142 AC: 2084 AN: 146426 Hom.: 57 Cov.: 29 AF XY: 0.0158 AC XY: 1126 AN XY: 71140

African (AFR) AF: 0.0167 AC: 658 AN: 39296

American (AMR) AF: 0.00514 AC: 74 AN: 14406

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 73 AN: 3410

East Asian (EAS) AF: 0.130 AC: 607 AN: 4654

South Asian (SAS) AF: 0.0405 AC: 171 AN: 4224

European-Finnish (FIN) AF: 0.0241 AC: 245 AN: 10182

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00322 AC: 216 AN: 67094

Other (OTH) AF: 0.0175 AC: 35 AN: 2004

Alfa AF: 0.0112 Hom.: 21

Bravo AF: 0.0134

ESP6500AA AF: 0.0226 AC: 39

ESP6500EA AF: 0.00455 AC: 18

ExAC AF: 0.0270 AC: 3229

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (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	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	-0.67	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.0
DANN	Benign	0.84
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.39
Vest4		0.058
MPC		0.21
ClinPred		0.0024	T
GERP RS		2.4
Mutation Taster		=99/1	polymorphism (auto)

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: rs72650053; hg19: chr2-179528068; COSMIC: COSV59894987; COSMIC: COSV59894987;