rs1236045684

Variant names:

• chr2-178658746-G-A
• rs1236045684
• NM_001267550.2:c.37502C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178658746-G-A
• chr2-178658746-G-T

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.37502C>T​(p.Pro12501Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P12501P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.0580
• 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=0.10177502).
• BP6: Variant 2-178658746-G-A is Benign according to our data. Variant chr2-178658746-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 467082.

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.37502C>T	p.Pro12501Leu	missense	Exon 183 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34522+259C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31741+259C>T		intron	N/A	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.37502C>T	p.Pro12501Leu	missense	Exon 183 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37502C>T	p.Pro12501Leu	missense	Exon 183 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37226C>T	p.Pro12409Leu	missense	Exon 181 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000981 AC: 14 AN: 142780 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000413

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000635 AC: 5 AN: 78796 AF XY: 0.0000260

Gnomad AFR exome AF: 0.000315

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000646

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000265 AC: 38 AN: 1433748 Hom.: 0 Cov.: 29 AF XY: 0.0000182 AC XY: 13 AN XY: 714016

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

African (AFR) AF: 0.0000606 AC: 2 AN: 33016

American (AMR) AF: 0.0000451 AC: 2 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39512

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00000918 AC: 10 AN: 1089464

Other (OTH) AF: 0.000270 AC: 16 AN: 59270

⚠️ 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 AF: 0.0000981 AC: 14 AN: 142780 Hom.: 0 Cov.: 19 AF XY: 0.0000725 AC XY: 5 AN XY: 68980

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

African (AFR) AF: 0.000180 AC: 7 AN: 38948

American (AMR) AF: 0.000143 AC: 2 AN: 13990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.000413 AC: 2 AN: 4840

South Asian (SAS) AF: 0.00 AC: 0 AN: 4166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.0000464 AC: 3 AN: 64614

Other (OTH) AF: 0.00 AC: 0 AN: 1944

⚠️ 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: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.80
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.058
Vest4		0.15
MVP		0.49
MPC		0.15
ClinPred		0.030	T
GERP RS		3.5
Mutation Taster		=89/11	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: rs1236045684; hg19: chr2-179523473;