rs77853750

Variant names:

• chr2-178553688-T-A
• rs77853750
• NM_001267550.2:c.89317A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178553688-T-A
• chr2-178553688-T-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.89317A>T​(p.Ile29773Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,872 control chromosomes in the GnomAD database, including 47 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 2.71
• Publications: 6 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004861504).
• BP6: Variant 2-178553688-T-A is Benign according to our data. Variant chr2-178553688-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47488.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 = 0.0101 (1537/152304) while in subpopulation AFR AF = 0.0343 (1426/41570). AF 95% confidence interval is 0.0328. There are 20 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.89317A>T	p.Ile29773Leu	missense	Exon 334 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.84394A>T	p.Ile28132Leu	missense	Exon 284 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.81613A>T	p.Ile27205Leu	missense	Exon 283 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.89317A>T	p.Ile29773Leu	missense	Exon 334 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.89161A>T	p.Ile29721Leu	missense	Exon 332 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.89041A>T	p.Ile29681Leu	missense	Exon 332 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152186 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00253 AC: 629 AN: 248516 AF XY: 0.00209

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00103 AC: 1512 AN: 1461568 Hom.: 27 Cov.: 33 AF XY: 0.000897 AC XY: 652 AN XY: 727064

African (AFR) AF: 0.0351 AC: 1175 AN: 33476

American (AMR) AF: 0.00208 AC: 93 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111792

Other (OTH) AF: 0.00250 AC: 151 AN: 60368

GnomAD4 genome AF: 0.0101 AC: 1537 AN: 152304 Hom.: 20 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74474

African (AFR) AF: 0.0343 AC: 1426 AN: 41570

American (AMR) AF: 0.00504 AC: 77 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00144 Hom.: 4

Bravo AF: 0.0119

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0321 AC: 129

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00308 AC: 373

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	0.077
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.69
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N
PhyloP100		2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.076
Sift	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.55		Gain of catalytic residue at I28132 (P = 0.0335)
MVP		0.47
MPC		0.083
ClinPred		0.060	T
GERP RS		5.6
Mutation Taster		=91/9	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: rs77853750; hg19: chr2-179418415;