rs192953152

Variant names:

• chr2-178616934-T-C
• rs192953152
• NM_001267550.2:c.47955A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_001267550.2(TTN):​c.47955A>G​(p.Pro15985Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.869
• 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]

ENSG00000271141 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-178616934-T-C is Benign according to our data. Variant chr2-178616934-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.869 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000541 (79/1460722) while in subpopulation AFR AF = 0.0021 (70/33398). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAdExome4. There are 30 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.47955A>G	p.Pro15985Pro	synonymous	Exon 256 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.43032A>G	p.Pro14344Pro	synonymous	Exon 206 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.40251A>G	p.Pro13417Pro	synonymous	Exon 205 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.47955A>G	p.Pro15985Pro	synonymous	Exon 256 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.47799A>G	p.Pro15933Pro	synonymous	Exon 254 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.47679A>G	p.Pro15893Pro	synonymous	Exon 254 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000428 AC: 65 AN: 151868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 247672 AF XY: 0.0000819

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.0000871

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 AF: 0.0000541 AC: 79 AN: 1460722 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 726654

African (AFR) AF: 0.00210 AC: 70 AN: 33398

American (AMR) AF: 0.0000895 AC: 4 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111252

Other (OTH) AF: 0.0000829 AC: 5 AN: 60308

GnomAD4 genome AF: 0.000434 AC: 66 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38 AN XY: 74284

African (AFR) AF: 0.00154 AC: 64 AN: 41524

American (AMR) AF: 0.000131 AC: 2 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67888

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000510

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.71
PhyloP100		0.87
Mutation Taster		=63/37	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: rs192953152; hg19: chr2-179481661;