2-178659011-G-C

Variant names:

• chr2-178659011-G-C
• rs1060500552
• NM_001267550.2:c.37447C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001267550.2(TTN):​c.37447C>G​(p.Pro12483Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12483H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000069 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.976
• Publications: 0 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06730196).

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.37447C>G	p.Pro12483Ala	missense	Exon 182 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34516C>G	p.Pro11506Ala	missense	Exon 156 of 313	NP_001243779.1
	TTN	NM_133378.4		c.31735C>G	p.Pro10579Ala	missense	Exon 155 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.37447C>G	p.Pro12483Ala	missense	Exon 182 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.37447C>G	p.Pro12483Ala	missense	Exon 182 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.37171C>G	p.Pro12391Ala	missense	Exon 180 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 6 AN: 100892 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.000142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000423

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000414 AC: 2 AN: 48346 AF XY: 0.0000415

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000576

Gnomad OTH exome AF: 0.000691

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000107 AC: 64 AN: 597266 Hom.: 0 Cov.: 8 AF XY: 0.000103 AC XY: 32 AN XY: 309474

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000189 AC: 3 AN: 15888

American (AMR) AF: 0.0000494 AC: 1 AN: 20240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14786

East Asian (EAS) AF: 0.00 AC: 0 AN: 32432

South Asian (SAS) AF: 0.00 AC: 0 AN: 48950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2286

European-Non Finnish (NFE) AF: 0.000153 AC: 59 AN: 386584

Other (OTH) AF: 0.0000322 AC: 1 AN: 31024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000693 AC: 7 AN: 100994 Hom.: 0 Cov.: 12 AF XY: 0.000105 AC XY: 5 AN XY: 47502

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000177 AC: 5 AN: 28252

American (AMR) AF: 0.00 AC: 0 AN: 9310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 4028

South Asian (SAS) AF: 0.00 AC: 0 AN: 2790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000423 AC: 2 AN: 47292

Other (OTH) AF: 0.00 AC: 0 AN: 1302

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000026105), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 28, 2016

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

Jul 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.3
DANN	Benign	0.62
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.98
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.13
Sift	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.28		Loss of glycosylation at P11506 (P = 0.0259)
MVP		0.15
MPC		0.082
ClinPred		0.037	T
GERP RS		2.0
Mutation Taster		=92/8	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: rs1060500552; hg19: chr2-179523738;