chr2-178659061-G-A

Variant names:

• chr2-178659061-G-A
• rs727503632
• NM_001267550.2:c.37397C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001267550.2(TTN):​c.37397C>T​(p.Pro12466Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00033 (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: 1.44
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29856032).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.37397C>T	p.Pro12466Leu	missense	Exon 182 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34466C>T	p.Pro11489Leu	missense	Exon 156 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31685C>T	p.Pro10562Leu	missense	Exon 155 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.37397C>T	p.Pro12466Leu	missense	Exon 182 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37397C>T	p.Pro12466Leu	missense	Exon 182 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37121C>T	p.Pro12374Leu	missense	Exon 180 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 15 AN: 106278 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0000335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00464

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000328 AC: 271 AN: 826512 Hom.: 0 Cov.: 11 AF XY: 0.000441 AC XY: 184 AN XY: 416830

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

African (AFR) AF: 0.0000481 AC: 1 AN: 20808

American (AMR) AF: 0.00 AC: 0 AN: 20806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16388

East Asian (EAS) AF: 0.00 AC: 0 AN: 33568

South Asian (SAS) AF: 0.00476 AC: 256 AN: 53792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44700

Middle Eastern (MID) AF: 0.000362 AC: 1 AN: 2766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 594814

Other (OTH) AF: 0.000334 AC: 13 AN: 38870

⚠️ 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: 0.000141 AC: 15 AN: 106386 Hom.: 0 Cov.: 12 AF XY: 0.000199 AC XY: 10 AN XY: 50342

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

African (AFR) AF: 0.0000334 AC: 1 AN: 29956

American (AMR) AF: 0.00 AC: 0 AN: 10078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2684

East Asian (EAS) AF: 0.00 AC: 0 AN: 4244

South Asian (SAS) AF: 0.00466 AC: 14 AN: 3002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 48372

Other (OTH) AF: 0.00 AC: 0 AN: 1386

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000169 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.86
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.31	D
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.36
Sift	Benign	0.056	T
Polyphen		0.95	P
Vest4		0.24
MutPred		0.41		Loss of ubiquitination at K11491 (P = 0.1612)
MVP		0.61
MPC		0.47
ClinPred		0.47	T
GERP RS		3.8
Mutation Taster		=85/15	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: rs727503632; hg19: chr2-179523788;