2-178662163-G-C

Variant names:

• chr2-178662163-G-C
• rs973940125
• NM_001267550.2:c.37099C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.37099C>G​(p.Pro12367Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000057 (0 hom., cov: 9)
  • Exomes 𝑓: 0.000068 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.51
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090850234).

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.37099C>G	p.Pro12367Ala	missense	Exon 178 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34354+803C>G		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31573+803C>G		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.37099C>G	p.Pro12367Ala	missense	Exon 178 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.37099C>G	p.Pro12367Ala	missense	Exon 178 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.36823C>G	p.Pro12275Ala	missense	Exon 176 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000569 AC: 4 AN: 70350 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.0000630

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: 0.0000806

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 17054 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000678 AC: 47 AN: 693682 Hom.: 0 Cov.: 9 AF XY: 0.0000570 AC XY: 20 AN XY: 351182

African (AFR) AF: 0.00 AC: 0 AN: 15704

American (AMR) AF: 0.000165 AC: 3 AN: 18236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15218

East Asian (EAS) AF: 0.00 AC: 0 AN: 28334

South Asian (SAS) AF: 0.00 AC: 0 AN: 42408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2342

European-Non Finnish (NFE) AF: 0.0000845 AC: 43 AN: 508964

Other (OTH) AF: 0.0000301 AC: 1 AN: 33256

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000569 AC: 4 AN: 70350 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 31942

African (AFR) AF: 0.0000630 AC: 1 AN: 15866

American (AMR) AF: 0.00 AC: 0 AN: 5996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2002

East Asian (EAS) AF: 0.00 AC: 0 AN: 1906

South Asian (SAS) AF: 0.00 AC: 0 AN: 1440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.0000806 AC: 3 AN: 37230

Other (OTH) AF: 0.00 AC: 0 AN: 858

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TTN-related disorder Uncertain:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTN c.37099C>G variant is predicted to result in the amino acid substitution p.Pro12367Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0073% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant falls within a highly paralogous region, and therefore allele frequency data should be interpreted with caution. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Feb 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.19
DANN	Benign	0.67
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.091	T
PhyloP100		-1.5
Vest4		0.11
MVP		0.45
GERP RS		2.1
Mutation Taster		=97/3	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: rs973940125; hg19: chr2-179526890;