chr2-178598657-G-A

Variant names:

• chr2-178598657-G-A
• rs375979145
• NM_001267550.2:c.56963-3C>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACGS-UK Somatic Oncogenicity v2025). B3_Supporting

The NM_001267550.2(TTN):c.56963-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The gene TTN is a known oncogene (CancerMine: 4 oncogene, 1 driver citations). The gene TTN is a cancer driver gene (CancerMine: 4 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.0000231 (AC=37) in the gnomAD database across 1,601,510 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00305. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.546
• 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• TTN-related myopathy, dominant-negative TTNsv

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• familial hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Splice-region variant — splicing algorithms predict no impact on splicing; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TTN NM_001267550.2	MANE Select	c.56963-3C>T	splice_regionintron	Intron 291 of 362	Prot: NP_001254479.2 UniProt:
	TTN NM_001256850.1		c.52040-3C>T	splice_regionintron	Intron 241 of 312	Prot: NP_001243779.1 UniProt:
	TTN NM_133378.4		c.49259-3C>T	splice_regionintron	Intron 240 of 311	Prot: NP_596869.4 UniProt:

TTN NM_001267550.2

MANE Select

HGVSc / HGVSpc.56963-3C>T

Exon rankIntron 291 of 362

splice_regionintron

Prot: NP_001254479.2UniProt: Q8WZ42-12

TTN NM_001256850.1

HGVSc / HGVSpc.52040-3C>T

Exon rankIntron 241 of 312

splice_regionintron

Prot: NP_001243779.1UniProt: Q8WZ42-1

TTN NM_133378.4

HGVSc / HGVSpc.49259-3C>T

Exon rankIntron 240 of 311

splice_regionintron

Prot: NP_596869.4UniProt: Q8WZ42-11

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TTN ENST00000589042.5	TSL:5MANE Select	c.56963-3C>T	splice_regionintron	Intron 291 of 362	Prot: ENSP00000467141.1 UniProt:
	TTN ENST00000446966.2	TSL:1	c.56807-3C>T	splice_regionintron	Intron 289 of 360	Prot: ENSP00000408004.2 UniProt:
	TTN ENST00000436599.2	TSL:1	c.56687-3C>T	splice_regionintron	Intron 289 of 360	Prot: ENSP00000405517.2 UniProt:

TTN ENST00000589042.5

TSL:5MANE Select

HGVSc / HGVSpc.56963-3C>T

Exon rankIntron 291 of 362

splice_regionintron

Prot: ENSP00000467141.1UniProt: Q8WZ42-12

TTN ENST00000446966.2

TSL:1

HGVSc / HGVSpc.56807-3C>T

Exon rankIntron 289 of 360

splice_regionintron

Prot: ENSP00000408004.2UniProt: A0A1B0GXE3

TTN ENST00000436599.2

TSL:1

HGVSc / HGVSpc.56687-3C>T

Exon rankIntron 289 of 360

splice_regionintron

Prot: ENSP00000405517.2UniProt: A0A0C4DG59

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:152018	Cov:32
GnomAD2 exomes	AF: 0.0000213	AC:5	Hom:	AN:234986	Cov:
GnomAD4 exome	AF: 0.0000248	AC:36	Hom:0	AN:1449492	Cov:32
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:152018	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000839	AC:2	Hom:0	AN:23832	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000843	AC:1	Hom:	AN:11866	Cov:
Qatari Genome	AF: 0.0114	AC:2	Hom:	AN:176	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000148	1	67384	0.0000226	3	132520

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.45
GPN-Star LLR	N/A	-0.18
GPN-Star score	N/A	0.18
Mutation Taster	N/A	80/20	polymorphism
PhyloP100	Benign	0.55

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.090
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs375979145;

hg19: chr2-179463384;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar