chr2-178659037-A-G

Variant names:

• chr2-178659037-A-G
• rs72650057
• NM_001267550.2:c.37421T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.37421T>C​(p.Ile12474Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1 O:1
• Conservation: PhyloP100: 1.08
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14793402).
• BP6: Variant 2-178659037-A-G is Benign according to our data. Variant chr2-178659037-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166094.

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.37421T>C	p.Ile12474Thr	missense	Exon 182 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34490T>C	p.Ile11497Thr	missense	Exon 156 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31709T>C	p.Ile10570Thr	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.37421T>C	p.Ile12474Thr	missense	Exon 182 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37421T>C	p.Ile12474Thr	missense	Exon 182 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37145T>C	p.Ile12382Thr	missense	Exon 180 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 14 AN: 105270 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000203

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: 0.000186

Gnomad OTH AF: 0.000753

GnomAD2 exomes AF: 0.000131 AC: 7 AN: 53246 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000496

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000146 AC: 119 AN: 814744 Hom.: 0 Cov.: 11 AF XY: 0.000146 AC XY: 60 AN XY: 411654

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

African (AFR) AF: 0.0000974 AC: 2 AN: 20526

American (AMR) AF: 0.000320 AC: 7 AN: 21884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16466

East Asian (EAS) AF: 0.0000298 AC: 1 AN: 33578

South Asian (SAS) AF: 0.0000183 AC: 1 AN: 54708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45242

Middle Eastern (MID) AF: 0.00183 AC: 5 AN: 2732

European-Non Finnish (NFE) AF: 0.000158 AC: 92 AN: 581136

Other (OTH) AF: 0.000286 AC: 11 AN: 38472

⚠️ 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: 0.000133 AC: 14 AN: 105376 Hom.: 0 Cov.: 12 AF XY: 0.000100 AC XY: 5 AN XY: 49876

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

African (AFR) AF: 0.0000676 AC: 2 AN: 29602

American (AMR) AF: 0.000202 AC: 2 AN: 9884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2668

East Asian (EAS) AF: 0.00 AC: 0 AN: 4226

South Asian (SAS) AF: 0.00 AC: 0 AN: 2988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.000186 AC: 9 AN: 48416

Other (OTH) AF: 0.000742 AC: 1 AN: 1348

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000845498), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000184 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.77
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.58	T
PhyloP100		1.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Benign	0.33	T
Polyphen		0.025	B
Vest4		0.20
MutPred		0.37		Gain of phosphorylation at I11497 (P = 0.0022)
MVP		0.47
MPC		0.26
ClinPred		0.021	T
GERP RS		4.1
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72650057; hg19: chr2-179523764;