rs377529060

Variant names:

• chr2-178590449-G-A
• rs377529060
• NM_001267550.2:c.61276C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000589042.5(TTN):​c.61276C>T​(p.Leu20426Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (1 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 3.82
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040632695).
• BP6: Variant 2-178590449-G-A is Benign according to our data. Variant chr2-178590449-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 332818.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.61276C>T	p.Leu20426Phe	missense	Exon 304 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.56353C>T	p.Leu18785Phe	missense	Exon 254 of 313	NP_001243779.1
	TTN	NM_133378.4		c.53572C>T	p.Leu17858Phe	missense	Exon 253 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.61276C>T	p.Leu20426Phe	missense	Exon 304 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.61120C>T	p.Leu20374Phe	missense	Exon 302 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.61000C>T	p.Leu20334Phe	missense	Exon 302 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152012 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000971

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000847 AC: 21 AN: 247964 AF XY: 0.0000595

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460846 Hom.: 1 Cov.: 37 AF XY: 0.0000179 AC XY: 13 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.000480 AC: 19 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111420

Other (OTH) AF: 0.000265 AC: 16 AN: 60340

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000974 AC: 5 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000827 AC: 10

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.95
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Benign	0.062	T
Polyphen		0.22	B
Vest4		0.34
MutPred		0.46		Loss of catalytic residue at L18785 (P = 0.0864)
MVP		0.36
MPC		0.11
ClinPred		0.063	T
GERP RS		6.1
Mutation Taster		=94/6	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: rs377529060; hg19: chr2-179455176;