rs182428755

Variant names:

• chr2-178675734-G-T
• rs182428755
• NM_001267550.2:c.34474C>A
• TTN p.Pro11492Thr

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.34474C>A​(p.Pro11492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,437,438 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (29 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.672
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054418445).
• BP6: Variant 2-178675734-G-T is Benign according to our data. Variant chr2-178675734-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00363 (551/151892) while in subpopulation NFE AF = 0.00494 (335/67866). AF 95% confidence interval is 0.0045. There are 2 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.34474C>A	p.Pro11492Thr	missense	Exon 149 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.33415+187C>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.30634+187C>A		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.34474C>A	p.Pro11492Thr	missense	Exon 149 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.34474C>A	p.Pro11492Thr	missense	Exon 149 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34198C>A	p.Pro11400Thr	missense	Exon 147 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 551 AN: 151774 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.0312

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00481

GnomAD2 exomes AF: 0.00449 AC: 324 AN: 72170 AF XY: 0.00443

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00326

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00563

GnomAD4 exome AF: 0.00629 AC: 8086 AN: 1285546 Hom.: 29 Cov.: 30 AF XY: 0.00615 AC XY: 3847 AN XY: 625506

African (AFR) AF: 0.000990 AC: 28 AN: 28284

American (AMR) AF: 0.00286 AC: 61 AN: 21330

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 629 AN: 20040

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34638

South Asian (SAS) AF: 0.000241 AC: 14 AN: 58058

European-Finnish (FIN) AF: 0.000207 AC: 6 AN: 29024

Middle Eastern (MID) AF: 0.00488 AC: 19 AN: 3896

European-Non Finnish (NFE) AF: 0.00669 AC: 6938 AN: 1036736

Other (OTH) AF: 0.00728 AC: 390 AN: 53540

GnomAD4 genome AF: 0.00363 AC: 551 AN: 151892 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 262 AN XY: 74272

African (AFR) AF: 0.00123 AC: 51 AN: 41472

American (AMR) AF: 0.00269 AC: 41 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 108 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 335 AN: 67866

Other (OTH) AF: 0.00476 AC: 10 AN: 2102

Alfa AF: 0.00467 Hom.: 3

Bravo AF: 0.00389

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0054	T
PhyloP100		0.67
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs182428755;

hg19: chr2-179540461;