rs72646881

Variant names:

• chr2-178577190-T-C
• rs72646881
• NM_001267550.2:c.69145A>G

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.69145A>G​(p.Ile23049Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,612,912 control chromosomes in the GnomAD database, including 532 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I23049T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (272 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (260 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.58
• Publications: 8 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]

ENSG00000271011 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001280725).
• BP6: Variant 2-178577190-T-C is Benign according to our data. Variant chr2-178577190-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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.69145A>G	p.Ile23049Val	missense	Exon 324 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.64222A>G	p.Ile21408Val	missense	Exon 274 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.61441A>G	p.Ile20481Val	missense	Exon 273 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.69145A>G	p.Ile23049Val	missense	Exon 324 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.68989A>G	p.Ile22997Val	missense	Exon 322 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.68869A>G	p.Ile22957Val	missense	Exon 322 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4977 AN: 151866 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.00867 AC: 2146 AN: 247570 AF XY: 0.00664

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000697

Gnomad OTH exome AF: 0.00417

GnomAD4 exome AF: 0.00383 AC: 5593 AN: 1460928 Hom.: 260 Cov.: 35 AF XY: 0.00335 AC XY: 2433 AN XY: 726750

African (AFR) AF: 0.119 AC: 3988 AN: 33450

American (AMR) AF: 0.00606 AC: 271 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00697 AC: 182 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53352

Middle Eastern (MID) AF: 0.00643 AC: 37 AN: 5756

European-Non Finnish (NFE) AF: 0.000533 AC: 592 AN: 1111494

Other (OTH) AF: 0.00829 AC: 500 AN: 60320

GnomAD4 genome AF: 0.0328 AC: 4992 AN: 151984 Hom.: 272 Cov.: 32 AF XY: 0.0320 AC XY: 2373 AN XY: 74268

African (AFR) AF: 0.113 AC: 4682 AN: 41460

American (AMR) AF: 0.0130 AC: 198 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67952

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0128 Hom.: 209

Bravo AF: 0.0379

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.103 AC: 402

ESP6500EA AF: 0.000966 AC: 8

ExAC AF: 0.0107 AC: 1294

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000831

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.89
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	N
PhyloP100		1.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.090
Sift	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.071
ClinPred		0.0095	T
GERP RS		3.2
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72646881; hg19: chr2-179441917;