rs72647877

Variant names:

• chr2-178777435-T-C
• rs72647877
• NM_001267550.2:c.4630A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.4630A>G​(p.Ile1544Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,760 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (47 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 2.70
• Publications: 10 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]

LOC101927055 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028096437).
• BP6: Variant 2-178777435-T-C is Benign according to our data. Variant chr2-178777435-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1779/152300) while in subpopulation AFR AF = 0.0349 (1451/41566). AF 95% confidence interval is 0.0334. There are 30 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.4630A>G	p.Ile1544Val	missense	Exon 26 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.4630A>G	p.Ile1544Val	missense	Exon 26 of 313	NP_001243779.1
	TTN	NM_133378.4		c.4630A>G	p.Ile1544Val	missense	Exon 26 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.4630A>G	p.Ile1544Val	missense	Exon 26 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.4630A>G	p.Ile1544Val	missense	Exon 26 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.4354A>G	p.Ile1452Val	missense	Exon 24 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1776 AN: 152182 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00504 AC: 1259 AN: 249930 AF XY: 0.00428

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00444

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00592

GnomAD4 exome AF: 0.00260 AC: 3793 AN: 1461460 Hom.: 47 Cov.: 34 AF XY: 0.00256 AC XY: 1859 AN XY: 727026

African (AFR) AF: 0.0386 AC: 1290 AN: 33462

American (AMR) AF: 0.00501 AC: 224 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 904 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5762

European-Non Finnish (NFE) AF: 0.000778 AC: 865 AN: 1111842

Other (OTH) AF: 0.00621 AC: 375 AN: 60368

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152300 Hom.: 30 Cov.: 33 AF XY: 0.0116 AC XY: 862 AN XY: 74464

African (AFR) AF: 0.0349 AC: 1451 AN: 41566

American (AMR) AF: 0.00686 AC: 105 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68020

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00509 Hom.: 41

Bravo AF: 0.0137

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00514 AC: 624

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	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	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	0.065
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.85
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.065
Sift	Benign	0.52	T
Sift4G	Uncertain	0.047	D
Polyphen		0.0010	B
Vest4		0.16
MVP		0.37
MPC		0.071
ClinPred		0.0025	T
GERP RS		3.5
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72647877; hg19: chr2-179642162; COSMIC: COSV99045820; COSMIC: COSV99045820;