rs534339525

Variant names:

• chr2-178677285-G-A
• rs534339525
• NM_001267550.2:c.34294C>T

Variant summary

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

The NM_001267550.2(TTN):​c.34294C>T​(p.Pro11432Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,168,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 26)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.42
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05460459).
• BP6: Variant 2-178677285-G-A is Benign according to our data. Variant chr2-178677285-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238747.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.34294C>T	p.Pro11432Ser	missense splice_region	Exon 147 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.33340+336C>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.30559+336C>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.34294C>T	p.Pro11432Ser	missense splice_region	Exon 147 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.34294C>T	p.Pro11432Ser	missense splice_region	Exon 147 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.34018C>T	p.Pro11340Ser	missense splice_region	Exon 145 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 56 AN: 135374 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000553

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00714

Gnomad NFE AF: 0.0000611

Gnomad OTH AF: 0.00107

GnomAD4 exome AF: 0.0000648 AC: 67 AN: 1033330 Hom.: 0 Cov.: 30 AF XY: 0.0000596 AC XY: 29 AN XY: 486812

African (AFR) AF: 0.000432 AC: 9 AN: 20830

American (AMR) AF: 0.000146 AC: 1 AN: 6830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12714

East Asian (EAS) AF: 0.00 AC: 0 AN: 20892

South Asian (SAS) AF: 0.00 AC: 0 AN: 18898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17530

Middle Eastern (MID) AF: 0.00151 AC: 4 AN: 2654

European-Non Finnish (NFE) AF: 0.0000515 AC: 46 AN: 892736

Other (OTH) AF: 0.000174 AC: 7 AN: 40246

GnomAD4 genome AF: 0.000406 AC: 55 AN: 135448 Hom.: 1 Cov.: 26 AF XY: 0.000430 AC XY: 28 AN XY: 65140

African (AFR) AF: 0.00119 AC: 41 AN: 34508

American (AMR) AF: 0.000553 AC: 7 AN: 12668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.00 AC: 0 AN: 4318

South Asian (SAS) AF: 0.00 AC: 0 AN: 4042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8034

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.0000611 AC: 4 AN: 65492

Other (OTH) AF: 0.00106 AC: 2 AN: 1890

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1

May 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Oct 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Mar 23, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.055	T
PhyloP100		1.4
Vest4		0.14
MVP		0.68
GERP RS		1.7
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs534339525; hg19: chr2-179542012;