2-178563493-C-T

Variant names:

• chr2-178563493-C-T
• rs779874042
• NM_001267550.2:c.82639G>A
• TTN p.Glu27547Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_001267550.2(TTN):c.82639G>A (p.Glu27547Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000103 (AC=15) in the gnomAD database across 1,461,516 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000107. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.86). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E27547= (synonymous): Likely_benign (ClinVar VariationId 510709, 2 stars)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86
• Publications: 3 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000107 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000161 by highest known P/LP ClinVar AF 0.000161) — PM2 supporting.

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.82639G>A p.Glu27547Lys	missense	Exon 326 of 363	Prot: NP_001254479.2 UniProt:
	TTN NM_001256850.1		c.77716G>A p.Glu25906Lys	missense	Exon 276 of 313	Prot: NP_001243779.1 UniProt:
	TTN NM_133378.4		c.74935G>A p.Glu24979Lys	missense	Exon 275 of 312	Prot: NP_596869.4 UniProt:

TTN NM_001267550.2

MANE Select

HGVSc / HGVSpc.82639G>Ap.Glu27547Lys

Exon rankExon 326 of 363

missense

Prot: NP_001254479.2UniProt: Q8WZ42-12

TTN NM_001256850.1

HGVSc / HGVSpc.77716G>Ap.Glu25906Lys

Exon rankExon 276 of 313

missense

Prot: NP_001243779.1UniProt: Q8WZ42-1

TTN NM_133378.4

HGVSc / HGVSpc.74935G>Ap.Glu24979Lys

Exon rankExon 275 of 312

missense

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.82639G>A p.Glu27547Lys	missense	Exon 326 of 363	Prot: ENSP00000467141.1 UniProt:
	TTN ENST00000446966.2	TSL:1	c.82483G>A p.Glu27495Lys	missense	Exon 324 of 361	Prot: ENSP00000408004.2 UniProt:
	TTN ENST00000436599.2	TSL:1	c.82363G>A p.Glu27455Lys	missense	Exon 324 of 361	Prot: ENSP00000405517.2 UniProt:

TTN ENST00000589042.5

TSL:5MANE Select

HGVSc / HGVSpc.82639G>Ap.Glu27547Lys

Exon rankExon 326 of 363

missense

Prot: ENSP00000467141.1UniProt: Q8WZ42-12

TTN ENST00000446966.2

TSL:1

HGVSc / HGVSpc.82483G>Ap.Glu27495Lys

Exon rankExon 324 of 361

missense

Prot: ENSP00000408004.2UniProt: A0A1B0GXE3

TTN ENST00000436599.2

TSL:1

HGVSc / HGVSpc.82363G>Ap.Glu27455Lys

Exon rankExon 324 of 361

missense

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:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.0000201	AC:5	Hom:	AN:248666	Cov:
GnomAD4 exome	AF: 0.0000103	AC:15	Hom:1	AN:1461516	Cov:37
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:36928	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000214	1	46816	0.0000276	2	72540

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

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.96
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.096
GPN-Star LLR	N/A	-9.2
GPN-Star score	N/A	9.2
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.36	T
Mutation Taster	N/A	90/10	polymorphism
MutationAssessor	Uncertain	2.3	M
PhyloP100	Pathogenic	7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.012	D
VESM-3B	Benign	-8.0

Showing 24 of 24 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	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: rs779874042;

hg19: chr2-179428220;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar